CASP8

Summary

CASP8 (caspase 8, HGNC:1509) is a protein-coding gene on chromosome 2q33.1, encoding Caspase-8 (Q14790). Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood. In precision oncology, CASP8 Overexpression confers sensitivity to Conatumumab in Ewing Sarcoma Of Bone (CIViC Level D).

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes composed of a prodomain, a large protease subunit, and a small protease subunit. Activation of caspases requires proteolytic processing at conserved internal aspartic residues to generate a heterodimeric enzyme consisting of the large and small subunits. This protein is involved in the programmed cell death induced by Fas and various apoptotic stimuli. The N-terminal FADD-like death effector domain of this protein suggests that it may interact with Fas-interacting protein FADD. This protein was detected in the insoluble fraction of the affected brain region from Huntington disease patients but not in those from normal controls, which implicated the role in neurodegenerative diseases. Many alternatively spliced transcript variants encoding different isoforms have been described, although not all variants have had their full-length sequences determined.

Source: NCBI Gene 841 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autoimmune lymphoproliferative syndrome type 2B (Definitive, ClinGen)
• GWAS associations: 25 (top 5% of genes corpus-wide)
• Clinical variants (ClinVar): 424 total — 19 pathogenic, 6 likely-pathogenic (top 8% of genes corpus-wide)
• GTEx eGene: eQTL in 44 tissues, sQTL in 28 (q < 0.05)
• Phenotypes (HPO): 28
• Drug target: yes — 1 curated mechanism-of-action drug; 2 molecules with ChEMBL bioactivity
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 11 cancer types (inferred from mutation patterns)
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 0.69 (unconstrained)
• MANE Select transcript: NM_001372051
• Interaction hub: 3,666 STRING partners (top 1% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1509
Approved symbol	CASP8
Name	caspase 8
Location	2q33.1
Locus type	gene with protein product
Status	Approved
Aliases	MCH5, MACH, FLICE, Casp-8
Ensembl gene	ENSG00000064012
Ensembl biotype	protein_coding
OMIM	601763
Entrez	841

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 30 protein_coding, 14 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000673742

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 9, TSL 3: 2, TSL 4: 1, TSL 5: 5

ENST00000673742, ENST00000264275, ENST00000323492, ENST00000339403, ENST00000358485, ENST00000392258, ENST00000392263, ENST00000413726, ENST00000429881, ENST00000432109, ENST00000437283, ENST00000440732, ENST00000444430, ENST00000447616, ENST00000450491, ENST00000471383, ENST00000490412, ENST00000490682, ENST00000696066, ENST00000696067, ENST00000696068, ENST00000696069, ENST00000696085, ENST00000696086, ENST00000696087, ENST00000957923, ENST00000982603, ENST00000982604, ENST00000982605, ENST00000982606, ENST00000982607, ENST00001019123, ENST00001019124, ENST00001019125, ENST00001019126, ENST00001019127, ENST00001019128, ENST00001019129, ENST00001019130, ENST00001019131, ENST00001019132, ENST00001019133, ENST00001019134, ENST00001019135, ENST00001019136, ENST00001019137, ENST00001019138, ENST00001019139, ENST00001144802

RefSeq mRNA: 40 — MANE Select: NM_001372051 NM_001080124, NM_001080125, NM_001228, NM_001372051, NM_001400642, NM_001400645, NM_001400648, NM_001400651, NM_001400653, NM_001400654, NM_001400655, NM_001400656, NM_001400657, NM_001400658, NM_001400659, NM_001400660, NM_001400661, NM_001400662, NM_001400663, NM_001400664, NM_001400665, NM_001400666, NM_001400667, NM_001400668, NM_001400669, NM_001400670, NM_001400671, NM_001400672, NM_001400673, NM_001400674, NM_001400675, NM_001400676, NM_001400677, NM_001400678, NM_001400679, NM_001400680, NM_001400750, NM_001400751, NM_033355, NM_033356

CCDS: CCDS2342, CCDS2343, CCDS2345, CCDS42798, CCDS42799, CCDS92922, CCDS92923

Canonical transcript exons

ENST00000673742 — 9 exons

Exon	Start	End
ENSE00001911342	201286459	201287709
ENSE00003460667	201266461	201266791
ENSE00003520750	201272638	201272776
ENSE00003601374	201274889	201274953
ENSE00003641950	201271516	201271621
ENSE00003663757	201284816	201285317
ENSE00003784438	201276827	201276968
ENSE00003787000	201272898	201272942
ENSE00003896682	201260536	201260613

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 96.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.3596 / max 2242.7075, expressed in 1783 samples.

Highest expression (Bgee): monocyte, mononuclear cell, leukocyte, blood, granulocyte.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CASP8 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 44 tissues and its splicing (sQTL) in 28 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 72 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	eqtl	1.5e-107	+0.72	2:201291331:T:C
Adipose Subcutaneous	eqtl	1.0e-91	+0.63	2:201288355:T:G
Skin Not Sun Exposed Suprapubic	eqtl	7.3e-88	+0.68	2:201286716:G:C
Cells Cultured fibroblasts	eqtl	2.5e-83	+0.60	2:201288355:T:G
Lung	eqtl	1.9e-73	+0.56	2:201286716:G:C
Adipose Visceral Omentum	eqtl	1.6e-71	+0.55	2:201286716:G:C
Whole Blood	eqtl	2.2e-68	+0.30	2:201286716:G:C
Breast Mammary Tissue	eqtl	1.1e-52	+0.61	2:201288355:T:G
Brain Cerebellar Hemisphere	eqtl	3.5e-46	-1.13	2:201288961:C:T
Adipose Subcutaneous	sqtl	1.1e-45	+0.64	2:201291331:T:C
Spleen	eqtl	5.0e-45	+0.65	2:201288355:T:G
Esophagus Mucosa	eqtl	2.1e-40	+0.38	2:201286716:G:C
Whole Blood	sqtl	3.2e-38	+0.45	2:201288355:T:G
Cells Cultured fibroblasts	sqtl	3.3e-37	+0.74	2:201288355:T:G
Lung	sqtl	1.4e-35	+0.61	2:201288355:T:G
Skin Sun Exposed Lower leg	sqtl	3.5e-35	+0.59	2:201288355:T:G
Pancreas	eqtl	6.5e-35	+0.67	2:201288355:T:G
Brain Cerebellum	eqtl	1.9e-32	-1.04	2:201279205:T:C
Muscle Skeletal	eqtl	4.5e-31	+0.37	2:201300114:A:C
Thyroid	sqtl	4.4e-30	+0.60	2:201300114:A:C

FANTOM5 promoters

showing 10 of 11 alternative TSS:

Promoter ID	TPM avg	Samples expressed
24677	14.2776	475
24667	6.3404	1011
24676	6.1534	572
24668	6.0605	852
24671	4.9224	1513
24672	1.0857	545
24673	0.4237	197
24675	0.4017	170
24674	0.2931	104
24670	0.2381	53

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.88	gold quality
mononuclear cell	CL:0000842	96.87	gold quality
leukocyte	CL:0000738	96.82	gold quality
blood	UBERON:0000178	96.51	gold quality
granulocyte	CL:0000094	95.75	gold quality
buccal mucosa cell	CL:0002336	94.89	gold quality
bone marrow cell	CL:0002092	93.61	gold quality
bone marrow	UBERON:0002371	93.26	gold quality
spleen	UBERON:0002106	93.03	gold quality
lymph node	UBERON:0000029	92.62	gold quality
vermiform appendix	UBERON:0001154	92.42	gold quality
colonic epithelium	UBERON:0000397	92.08	gold quality
rectum	UBERON:0001052	91.25	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.37	gold quality
epithelium of nasopharynx	UBERON:0001951	90.17	gold quality
nasopharynx	UBERON:0001728	90.16	gold quality
calcaneal tendon	UBERON:0003701	89.53	gold quality
tonsil	UBERON:0002372	89.33	gold quality
jejunal mucosa	UBERON:0000399	89.29	gold quality
small intestine	UBERON:0002108	89.10	gold quality
caecum	UBERON:0001153	88.89	gold quality
right lung	UBERON:0002167	88.68	gold quality
gall bladder	UBERON:0002110	88.15	gold quality
upper lobe of left lung	UBERON:0008952	88.03	gold quality
adrenal tissue	UBERON:0018303	88.02	gold quality
upper lobe of lung	UBERON:0008948	87.75	gold quality
right uterine tube	UBERON:0001302	87.20	gold quality
superficial temporal artery	UBERON:0001614	86.23	gold quality
thymus	UBERON:0002370	86.10	gold quality
esophagus mucosa	UBERON:0002469	85.85	gold quality
duodenum	UBERON:0002114	85.61	gold quality
colonic mucosa	UBERON:0000317	85.29	gold quality
endometrium	UBERON:0001295	85.28	gold quality
transverse colon	UBERON:0001157	85.23	gold quality
nasal cavity mucosa	UBERON:0001826	85.15	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.15	gold quality
sural nerve	UBERON:0015488	85.04	gold quality
intestine	UBERON:0000160	84.98	gold quality
germinal epithelium of ovary	UBERON:0001304	84.97	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.93	gold quality
lung	UBERON:0002048	84.86	gold quality
urinary bladder	UBERON:0001255	84.63	gold quality
right adrenal gland cortex	UBERON:0035827	84.46	gold quality
adrenal gland	UBERON:0002369	84.31	gold quality
left adrenal gland	UBERON:0001234	84.28	gold quality
adipose tissue	UBERON:0001013	84.22	gold quality
right adrenal gland	UBERON:0001233	84.04	gold quality
left adrenal gland cortex	UBERON:0035825	84.02	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.00	gold quality
adipose tissue of abdominal region	UBERON:0007808	83.97	gold quality
connective tissue	UBERON:0002384	83.93	gold quality
metanephros cortex	UBERON:0010533	83.88	gold quality
omental fat pad	UBERON:0010414	83.85	gold quality
oral cavity	UBERON:0000167	83.84	gold quality
peritoneum	UBERON:0002358	83.79	gold quality
lower lobe of lung	UBERON:0008949	83.65	gold quality
skin of hip	UBERON:0001554	83.59	gold quality
left uterine tube	UBERON:0001303	83.58	gold quality
large intestine	UBERON:0000059	83.54	gold quality
corpus epididymis	UBERON:0004359	83.45	gold quality
colon	UBERON:0001155	83.39	gold quality
right coronary artery	UBERON:0001625	83.36	gold quality
palpebral conjunctiva	UBERON:0001812	83.33	gold quality
trabecular bone tissue	UBERON:0002483	83.28	gold quality
nasal cavity epithelium	UBERON:0005384	83.17	gold quality
mucosa of transverse colon	UBERON:0004991	83.13	gold quality
esophagus	UBERON:0001043	82.98	gold quality
periodontal ligament	UBERON:0008266	82.98	gold quality
mucosa of stomach	UBERON:0001199	82.93	gold quality
body of stomach	UBERON:0001161	82.89	gold quality
minor salivary gland	UBERON:0001830	82.77	gold quality
adrenal cortex	UBERON:0001235	82.73	gold quality
stomach	UBERON:0000945	82.69	gold quality
descending thoracic aorta	UBERON:0002345	82.68	gold quality
esophagus squamous epithelium	UBERON:0006920	82.65	gold quality
skin of leg	UBERON:0001511	82.61	gold quality
skin of abdomen	UBERON:0001416	82.54	gold quality
upper leg skin	UBERON:0004262	82.44	gold quality
bronchial epithelial cell	CL:0002328	82.30	gold quality
mucosa of urinary bladder	UBERON:0001259	82.26	gold quality
stromal cell of endometrium	CL:0002255	82.25	gold quality
mouth mucosa	UBERON:0003729	82.12	gold quality
epithelium of esophagus	UBERON:0001976	82.11	gold quality
tendon	UBERON:0000043	82.08	gold quality
amniotic fluid	UBERON:0000173	82.01	gold quality
body of pancreas	UBERON:0001150	81.84	gold quality
gingival epithelium	UBERON:0001949	81.84	gold quality
liver	UBERON:0002107	81.81	gold quality
right lobe of liver	UBERON:0001114	81.68	gold quality
right lobe of thyroid gland	UBERON:0001119	81.65	gold quality
zone of skin	UBERON:0000014	81.53	gold quality
left lobe of thyroid gland	UBERON:0001120	81.53	gold quality
vagina	UBERON:0000996	81.47	gold quality
ectocervix	UBERON:0012249	81.39	gold quality
visceral pleura	UBERON:0002401	81.38	gold quality
thoracic aorta	UBERON:0001515	81.14	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.11	gold quality
uterus	UBERON:0000995	81.08	gold quality
parietal pleura	UBERON:0002400	81.07	gold quality
endocervix	UBERON:0000458	81.04	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.38
E-ENAD-17	no	421.01

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	44.1	low
Lymph node	tissue	26.3	high
Spleen	tissue	23.9	medium
Tonsil	tissue	22.8	high
Appendix	tissue	21.2	high
Thymus	tissue	17.4
Lung	tissue	15.0	high
Rectum	tissue	13.8	high
Small intestine	tissue	13.6	high
Duodenum	tissue	13.6	high
Urinary bladder	tissue	12.3	high
Colon	tissue	11.7	high
Fallopian tube	tissue	11.6	high
Liver	tissue	11.1	low
Stomach 1	tissue	10.9	medium
Breast	tissue	10.5	medium
Epididymis	tissue	10.1	high
Gallbladder	tissue	9.3	high
Kidney	tissue	8.8	high
Adipose tissue	tissue	8.7	medium
Smooth muscle	tissue	7.7	low
Cervix	tissue	7.6	medium
Skin 1	tissue	7.6	not detected
Placenta	tissue	7.4	high
Vagina	tissue	7.1	low
Ovary	tissue	6.7	medium
Esophagus	tissue	6.7	low
Endometrium 1	tissue	6.2	medium
Adrenal gland	tissue	6.2	medium
Prostate	tissue	5.5	medium
Seminal vesicle	tissue	5.4	low
Salivary gland	tissue	5.3	medium
Choroid plexus	tissue	5.2
Thyroid gland	tissue	5.2	low
Periaqueductal gray	tissue	3.8
Frontal cortex	tissue	3.7
Caudate putamen	tissue	3.5
Spinal cord	tissue	3.4
Heart muscle	tissue	3.3	low
Substantia nigra	tissue	3.2
Testis	tissue	2.9	high
Pons	tissue	2.9
Medulla oblongata	tissue	2.9
Superior colliculi	tissue	2.9
Hypothalamus	tissue	2.8
Hippocampus	tissue	2.8	low
Pituitary gland	tissue	2.7
Midbrain	tissue	2.6
Locus coeruleus	tissue	2.6
Septum	tissue	2.6
Nucleus accumbens	tissue	2.5
Thalamus	tissue	2.5
Parathyroid gland	tissue	2.4	high
Pancreas	tissue	2.2	medium
Tongue	tissue	2.1
Putamen	tissue	2.1
Corpus callosum	tissue	2.1
Basal ganglia	tissue	2.0	low
Amygdala	tissue	1.9
Hippocampal formation	tissue	1.9

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Blood vessel (6.1), Lateral funiculus (white matter) (5.4), Nucleus tractus solitarii (4.8), Superior vestibular nucleus (4.4), Anterior thalamic nucleus, ventral (4.2).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CEBPA, CEBPD, CREB1, DLL4, DNMT1, E2F1, ELF1, ETS1, FOXO1, FOXO3, IRF1, IRF2, JUN, MEN1, MYC, NFKB, NKX3-1, PARP1, RELA, RUNX3, SMAD5, SMAD7, SP1, SPI1, STAT1, TP53

miRNA regulators (miRDB)

Targeting CASP8 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 56 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-579-3P	99.86	71.66	3628

Functional genomics

gnomAD constraint: pLI 0.0125, LOEUF 0.695, missense Z 1.67 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000673742 — one region, missense o/e 0.82.

Literature-anchored findings (GeneRIF, showing 40)

• FADD/MORT1 and caspase-8 are recruited to TRAIL receptors 1 and 2 and are essential for apoptosis mediated by TRAIL receptor 2 (PMID:10894160)
• The activation of caspase-8, but not caspase-9, is necessary for Fas-induced apoptosis. Conversely, caspase-9, but not caspase-8, is important for UV-mediated shrunken morphology and apoptosis progression. (PMID:11431480)
• Our data indicate that the activation of caspase-8 at the DISC and hence CD95-mediated apoptosis induction shows a cell-specific requirement for intracellular glutathione (PMID:11734564)
• binding of FADD and caspase-8 to molluscum contagiosum virus MC159 v-FLIP is not sufficient for its antiapoptotic function (PMID:11752160)
• Results show that pro-apoptotic Hippi-Hip-1 heterodimers can recruit procaspase-8 into a complex of Hippi, Hip-1 and procaspase-8, and launch apoptosis through components of the ’extrinsic’ cell-death pathway. (PMID:11788820)
• Activation of caspase-8 is critical for sensitivity to cytotoxic anti-Fas antibody-induced apoptosis (PMID:11865194)
• Resistance to TRAIL in multiple myeloma cells arises from inhibition at the level of caspase-8 activation. Caspase-8 is the apical caspase of TRAIL signaling in MM cells. (PMID:11877293)
• caspase-8 activation is necessary but not sufficient for TRAIL-mediated apoptosis (PMID:11992615)
• lack of role in caspase-9 activation in Sendai virus-infected cells (PMID:12021264)
• alteration associated with nodal metastasis in non-small cell lung cancer (PMID:12037669)
• Sodium salicylate-triggered apoptosis in HL-60 cells depends on caspase-8 activation. (PMID:12041673)
• requirement in Hid-triggered apoptosis (PMID:12122017)
• CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells (PMID:12131184)
• CASP8 may function as a tumor suppressor gene in neuroendocrine lung tumors. (PMID:12170765)
• ARC at threonine 149 is phosphorylated by CK2; this phosphorylation targets ARC to mitochondria; ARC is able to bind to caspase-8 only when it is localized to mitochondria but not to the cytoplasm (PMID:12191471)
• Caspase-10 can not substitute for caspase-8, as the defect in apoptosis induction observed in caspase-8-deficient cells could not be rescued by overexpression of caspase-10. (PMID:12198154)
• Caspase-10 is recruited to and activated at the native TRAIL and CD95 death-inducing signalling complexes in a FADD-dependent manner but can not functionally substitute caspase-8. (PMID:12198154)
• Data show that FLIP-L promotes the first proteolytic cleavage of pro-caspase-8, but prevents further cleavage of the proenzyme. (PMID:12215447)
• Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency (PMID:12353035)
• caspase 3 activation and apoptosis are blocked by LIGHT protein in hepatocytes (PMID:12393901)
• Treatment of prostatic cell lines with TRAIL alone resulted in processing of FLIP (cellular) and initiated abortive CASP8 proteolysis. (PMID:12496481)
• CASP8 activity is triggered by TRAIL-R1 and TRAIL-R2 and continues to apoptosis. (PMID:12496482)
• caspase 8 is activated by boswellic acids in an apoptotic cascade (PMID:12507932)
• one or more distinct cellular mechanisms regulate Bid cleavage by caspases 8 and 3 in situ. (PMID:12598529)
• single amino acid substitutions at the dimer interface abrogate the activity of caspases-8 and -9 (PMID:12620239)
• caspase 8 induces apoptosis after activation by ASC protein (PMID:12646168)
• CASP8 cleavage product of BAP31 at the endoplasmic reticulum stimulates Ca(2+)-dependent mitochondrial fission, enhancing the release of cytochrome C in response to this initiator caspase. (PMID:12668660)
• Caspases responsible for parkin cleavage were identified by several experimental paradigms exploring the anti-Fas induced pathway and tnf-alpha pathway. (PMID:12692130)
• caspase 8 has a critical role in apoptosis in the death receptor pathway in small cell lung carcinoma cell lines (PMID:12700635)
• Caspase-8 mediates a mitochondrial amplification loop that is required for the optimal release of cytochrome c, mitochondrial permeability shift transition, & cell death during apoptosis induced by treatment with the microtubule-damaging agent paclitaxel. (PMID:12700660)
• Caspase 8-mediated cell death is central to the biological control of antigen-independent expansion of recent thymic emigrants from human cord blood. (PMID:12707329)
• caspase-8 and FADD are obligatory for TNF-mediated apoptosis but are not recruited to a TNF-induced membrane-bound receptor signaling complex; they must be activated elsewhere within the cell (PMID:12721308)
• Caspase-8 expression and proteolysis in human brain after severe intracranial hypertension. (PMID:12738800)
• caspase-8 promoter sustains basal activity through SP1 and ETS-like transcription factors and is up-regulated in a p53-dependent mechanism (PMID:12748179)
• identified for the first time a predominant role for the caspase-8/Bid pathway in signaling associated with hyperoxic lung injury and cell death in vivo and in vitro (PMID:12754217)
• caspase 8 has an essential role in BID cleavage, in the course of p53-dependent apoptosis triggered by fast neutrons in lymphoid cells (PMID:12804595)
• Caspase 8 expression is an important determinant of the response of neuroblastoma cells to Fas-mediated cell death. (PMID:12841868)
• Enzyme activation of CASP8 involves an alteration in the enzymatic properties of CASP8, while procaspase-8 molecules specifically process one another,mature caspases only cleave effector caspases. (PMID:12912912)
• TNFalpha and caspase 8 play roles in the regulation of MMP1 and MMP9 by interferon gamma (PMID:12960156)
• ARK5 suppresses the apoptosis induced by nutrient starvation and death receptors via inhibition of CASP8 activation. (PMID:13679856)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Casp8	ENSMUSG00000026029
rattus_norvegicus	Casp8	ENSRNOG00000012331
drosophila_melanogaster	Dronc	FBGN0026404
drosophila_melanogaster	Decay	FBGN0028381
caenorhabditis_elegans		WBGENE00000417
caenorhabditis_elegans		WBGENE00000819
caenorhabditis_elegans		WBGENE00000820
caenorhabditis_elegans	csp-3	WBGENE00000821

Paralogs (16): CASP10 (ENSG00000003400), CFLAR (ENSG00000003402), PYCARD (ENSG00000103490), CASP14 (ENSG00000105141), CASP2 (ENSG00000106144), CASP9 (ENSG00000132906), CASP1 (ENSG00000137752), CASP5 (ENSG00000137757), CASP6 (ENSG00000138794), CASP3 (ENSG00000164305), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CASP4 (ENSG00000196954), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1261423) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 102 distinct phenotype terms.

Mouse phenotype (MP)	Records
embryonic lethality, complete penetrance	4
abnormal heart morphology	2
abnormal liver morphology	2
small liver	2
enlarged spleen	2
wavy neural tube	2
premature death	2
abnormal blood circulation	2
abnormal kidney morphology	2
abnormal T cell physiology	2
abnormal vitelline vasculature morphology	2
abnormal T cell subpopulation ratio	2
decreased T cell number	2
decreased CD4-positive, alpha-beta T cell number	2
decreased CD8-positive, alpha-beta T cell number	2
embryonic lethality during organogenesis, complete penetrance	2
decreased leukocyte cell number	1
enlarged heart	1
thin ventricular wall	1
abnormal cell death	1
increased mast cell number	1
lymphoid hyperplasia	1
spleen hypoplasia	1
enlarged lymph nodes	1
abnormal lung morphology	1

+77 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	Q5IS54	99.6%	Diamond
Macaca fascicularis	Q2PFV2	96.0%	Diamond
Saimiri boliviensis boliviensis	Q5IS99	96.0%	Diamond
Mesocricetus auratus	Q60431	92.1%	Diamond
Oryctolagus cuniculus	Q8MJC3	90.6%	Diamond
Felis catus	Q8MJU1	89.9%	Diamond
Canis lupus familiaris	Q8MKI5	89.9%	Diamond
Sus scrofa	Q95ND5	88.8%	Diamond
Bos taurus	Q3T0P5	88.3%	Diamond
Caenorhabditis remanei	P45436	84.5%	Diamond
Gallus gallus	F1NV61	73.9%	Diamond
Spodoptera frugiperda	P89116	66.7%	Diamond
Xenopus laevis	P55866	59.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
FLACC1	protein-coding	130540
CATSPERT	protein-coding	151254
STRADB	protein-coding	55437
TRAK2	protein-coding	66008
CASP10	protein-coding	843
CFLAR	protein-coding	8837
CFLAR-AS1	ncRNA	65072

Protein

Protein identifiers

Caspase-8 — Q14790 (reviewed: Q14790)

Alternative names: Apoptotic cysteine protease, Apoptotic protease Mch-5, CAP4, FADD-homologous ICE/ced-3-like protease, FADD-like ICE, ICE-like apoptotic protease 5, MORT1-associated ced-3 homolog

All UniProt accessions (12): A0A8Q3SI66, A0A8Q3SID9, A0A8Q3WKY8, C3S3G0, C9JB29, E7EQ01, E7EQ06, E7ETB7, E7EVN1, Q14790, F8WF39, H7C0E2

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood. Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for FAS/CD95-mediated and TNFRSF1A-induced cell death. Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. Binding to the adapter molecule FADD recruits it to either receptor FAS/TNFRSF6 or TNFRSF1A. The resulting aggregate called the death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Also cleaves and activates BID, thereby promoting cytochrome C release from mitochrondria. In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at ‘Asp-324’, which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response. Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-C and -D (GSDMC and GSDMD, respectively): gasdermin cleavage promotes release of the N-terminal moiety that binds to membranes and forms pores, triggering pyroptosis. Initiates pyroptosis following inactivation of MAP3K7/TAK1. Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production. May participate in the Granzyme B (GZMB) cell death pathways. Cleaves PARP1 and PARP2. Independent of its protease activity, promotes cell migration following phosphorylation at Tyr-380. Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex. Acts as an inhibitor of the caspase cascade. Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.

Subunit / interactions. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 10 kDa (p10) subunit. Component of the death-induced signaling complex (DISC) composed of cell surface receptor FAS/CD95 or TNFRSF1A, adapter protein FADD and the CASP8 protease; recruitment of CASP8 to the complex is required for processing of CASP8 into the p18 and p10 subunits. Component of the AIM2 PANoptosome complex, a multiprotein complex that drives inflammatory cell death (PANoptosis). Interacts with CFLAR and PEA15. Interacts with TNFAIP8L2. Interacts with CASP8AP2. Interacts with RFFL and RNF34; negatively regulate CASP8 through proteasomal degradation. Interacts with NOL3; decreases CASP8 activity in a mitochondria localization- and phosphorylation-dependent manner and this interaction is dissociated by calcium. Interacts with UBR2ca. Interacts with RIPK1. Interacts with stimulated TNFRSF10B; this interaction is followed by CASP8 proteolytic cleavage and activation. Interacts (phosphorylated on Tyr-380) with PIK3R1. Interacts at the endoplasmic reticulum with a complex containing BCAP31, BAP29, BCL2 and/or BCL2L1. (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein vICA/UL36; this interaction inhibits CASP8 activation. (Microbial infection) Interacts with NleF from pathogenic E.coli. (Microbial infection) Interacts with molluscum contagiosum virus protein MC160. (Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 1/HHV-1 protein RIR1/ICP6 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation. (Microbial infection) Interacts (via RIP homotypic interaction motif) with herpes simplex virus 2/HHV-2 protein RIR1/ICP10 (via RIP homotypic interaction motif); this interaction prevents necroptosis activation.

Subcellular location. Cytoplasm. Nucleus. Cell projection. Lamellipodium.

Tissue specificity. Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle.

Post-translational modifications. Generation of the p10 and p18 subunits requires association with the death-inducing signaling complex (DISC), whereas additional processing is likely due to the autocatalytic activity of the activated protease. GZMB and CASP10 can be involved in these processing events. Phosphorylation on Ser-387 during mitosis by CDK1 inhibits activation by proteolysis and prevents apoptosis. Phosphorylation on Tyr-380 by SRC is mediated by interaction with the SRC SH2 domain and does not affect dimerization or recruitment to the death-inducing signaling complex (DISC) but negatively regulates DISC-mediated processing and activation of CASP8, down-regulating its proapoptotic function. Phosphorylation on Tyr-380 also enhances localization to lamellipodia in migrating cells. (Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP8 processing, preventing CASP8 activation and ability to mediate extrinsic apoptosis. (Microbial infection) Proteolytically cleaved by the cowpox virus CRMA death inhibitory protein.

Disease relevance. Caspase-8 deficiency (CASP8D) [MIM:607271] Disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. CASP8 activity is restricted by RIPK1. Inhibited by the effector protein NleF that is produced by pathogenic E.coli; this inhibits apoptosis.

Domain organisation. The catalytic domain is sufficient for recruitment to lamellipodia but catalytic activity is not necessary. Contains a N-terminal extension that is required for interaction with the BCAP31 complex.

Polymorphism. Genetic variations in CASP8 are associated with reduced risk of lung cancer [MIM:211980] in a population of Han Chinese subjects. Genetic variations are also associated with decreased risk of cancer of various other forms including esophageal, gastric, colorectal, cervical, and breast, acting in an allele dose-dependent manner.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the peptidase C14A family.

Isoforms (9)

UniProt ID	Names	Canonical?
Q14790-1	1, Alpha-1	yes
Q14790-2	2, Alpha-2, MCH5-beta
Q14790-3	3, Alpha-3
Q14790-4	4, Alpha-4
Q14790-5	5, Beta-1
Q14790-6	6, Beta-2
Q14790-7	7, Beta-3, 8L
Q14790-8	8, Beta-4
Q14790-9	9, 8L

RefSeq proteins (40): NP_001073593, NP_001073594, NP_001219, NP_001358980, NP_001387571, NP_001387574, NP_001387577, NP_001387580, NP_001387582, NP_001387583, NP_001387584, NP_001387585, NP_001387586, NP_001387587, NP_001387588, NP_001387589, NP_001387590, NP_001387591, NP_001387592, NP_001387593, NP_001387594, NP_001387595, NP_001387596, NP_001387597, NP_001387598, NP_001387599, NP_001387600, NP_001387601, NP_001387602, NP_001387603, NP_001387604, NP_001387605, NP_001387606, NP_001387607, NP_001387608, NP_001387609, NP_001387679, NP_001387680, NP_203519, NP_203520 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001309	Pept_C14_p20	Domain
IPR001875	DED_dom	Domain
IPR002138	Pept_C14_p10	Domain
IPR011029	DEATH-like_dom_sf	Homologous_superfamily
IPR011600	Pept_C14_caspase	Domain
IPR015917	Pept_C14A	Domain
IPR016129	Caspase_his_AS	Active_site
IPR029030	Caspase-like_dom_sf	Homologous_superfamily
IPR033139	Caspase_cys_AS	Active_site
IPR033170	Caspase-8_DED1	Domain

Pfam: PF00656, PF01335

Enzyme classification (BRENDA)

• EC 3.4.22.61 — caspase-8 (BRENDA: 19 organisms, 194 substrates, 116 inhibitors, 9 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-IETD-7-AMIDO-4-FLUOROMETHYLCOUMARIN	0.0206–0.0552	4
ACETYL-DEVD-7-AMIDO-4-METHYLCOUMARIN	0.004–0.007	2
AC-IETD-4-METHYLCOUMARIN 7-AMIDE	0.0045	1
ACETYL-IETD-4-NITROANILIDE	0.066	1

UniProt features (93 total): helix 24, strand 20, splice variant 10, modified residue 7, mutagenesis site 7, turn 7, sequence conflict 4, site 3, sequence variant 3, propeptide 2, chain 2, domain 2, active site 2

Structure

Experimental structures (PDB)

showing 30 of 36 structures by resolution:

PDB	Title	Method	Resolution (Å)
4JJ7	Caspase-3 specific unnatural amino acid-based peptides	X-RAY DIFFRACTION	1.18
1QTN	CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TETRAPEPTIDE INHIBITOR …	X-RAY DIFFRACTION	1.2
7LVM	CASP8 isoform B DED domain	X-RAY DIFFRACTION	1.47
6X8H	Caspase-8 in complex with AOMK inhibitor, Ac-DW3-KE, forms tetrahedral adduct	X-RAY DIFFRACTION	1.48
7LVJ	CASP8 isoform G DED domain	X-RAY DIFFRACTION	1.5
4PS1	Caspase-8 specific unnatural amino acid peptides	X-RAY DIFFRACTION	1.73
2Y1L	Caspase-8 in Complex with DARPin-8.4	X-RAY DIFFRACTION	1.8
3KJN	Caspase 8 bound to a covalent inhibitor	X-RAY DIFFRACTION	1.8
3KJQ	Caspase 8 with covalent inhibitor	X-RAY DIFFRACTION	1.8
3H11	Zymogen caspase-8:c-FLIPL protease domain complex	X-RAY DIFFRACTION	1.9
2C2Z	Crystal structure of caspase-8 in complex with aza-peptide Michael acceptor inhibitor	X-RAY DIFFRACTION	1.95
8YM5	Structure of Caspase-8/cFLIP death effector domain assembly	X-RAY DIFFRACTION	2.09
6AGW	Pro-domain of Caspase-8	X-RAY DIFFRACTION	2.09
4PRZ	Caspase-8 specific unnatural amino acid peptides	X-RAY DIFFRACTION	2.12
4ZBW	Crystal structure of death effector domain of Caspase8 in Homo Sapiens	X-RAY DIFFRACTION	2.2
8YM4	Structure of Caspase-8/cFLIP death effector domain assembly	X-RAY DIFFRACTION	2.34
1QDU	CRYSTAL STRUCTURE OF THE COMPLEX OF CASPASE-8 WITH THE TRIPEPTIDE KETONE INHIBITOR …	X-RAY DIFFRACTION	2.8
6PX9	Crystal structure of procaspase-8 in complex with covalent small molecule inhibitor 63-R	X-RAY DIFFRACTION	2.88
1F9E	CASPASE-8 SPECIFICITY PROBED AT SUBSITE S4: CRYSTAL STRUCTURE OF THE CASPASE-8-Z-DEVD-CHO	X-RAY DIFFRACTION	2.9
1I4E	CRYSTAL STRUCTURE OF THE CASPASE-8/P35 COMPLEX	X-RAY DIFFRACTION	3
2FUN	alternative p35-caspase-8 complex	X-RAY DIFFRACTION	3
8YD8	Structure of FADD/Caspase-8/cFLIP death effector domain assembly	X-RAY DIFFRACTION	3.11
5JQE	Crystal structure of caspase8 tDED	X-RAY DIFFRACTION	3.16
5H31	Structural basis for dimerization of the death effector domains of Caspase-8	X-RAY DIFFRACTION	3.17
8YM6	Structure of Caspase-8/cFLIP death effector domain assembly	X-RAY DIFFRACTION	3.3
8YD7	Structure of FADD/Caspase-8/cFLIP death effector domain assembly	X-RAY DIFFRACTION	3.32
8YNM	Structure of the Caspase-8/cFLIP death effector domain assembly	ELECTRON MICROSCOPY	3.49
8YNL	Structure of the Caspase-8/cFLIP death effector domain assembly	ELECTRON MICROSCOPY	3.55
5H33	Structural basis for dimerization of the death effector domains of Caspase-8	X-RAY DIFFRACTION	3.6
8YNK	Structure of the Caspase-8/cFLIP death effector domain assembly	ELECTRON MICROSCOPY	3.62

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14790-F1	82.37	0.49

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Predicted intracellular proteins, Cancer-related genes, Candidate cancer biomarkers, Mutated cancer genes, Mutational cancer driver genes, Disease related genes, Potential drug targets, Human disease related genes, Primary immunodeficiency

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; mitochondria; centriolar satellite; connecting piece; mid piece; principal piece

Antibody reliability (HPA): IH approved · IF uncertain

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (5)

Position	Role
384–385	cleavage; by autocatalytic cleavage
317
360
216–217	cleavage; by autocatalytic cleavage
374–375	cleavage; by casp6

Post-translational modifications (7)

Type	Positions
Phosphoserine	188, 211, 387
N6-acetyllysine	224
Phosphotyrosine	334, 380
(microbial infection) adp-riboxanated arginine	413

Mutagenesis-validated functional residues (7)

Position	Phenotype
73	abolishes binding to flash. induces nf-kappa-b activation.
360	does not affect localization to lamellipodia of migrating cells. prevents disc-mediated processing of casp8.
360	abolishes interaction with ubr2.
380	phosphomimetic mutant which does not affect interaction with pik3r1 or disc-mediated processing.
380	abolishes phosphorylation at this site. lack of efficient localization to lamellipodia and lack of promotion of cell migration. lack of …
387	impaired cdk1-mediated phosphorylation and enhanced apoptosis.
413	abolished adp-riboxanation by c.violaceum copc.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 59; 4 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

59 pathways:

ID	Pathway	Evidence
R-HSA-9693928	Defective RIPK1-mediated regulated necrosis ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-9645723	Diseases of programmed cell death ⚕	—
R-HSA-9686347	Microbial modulation of RIPK1-mediated regulated necrosis ⚕	—
R-HSA-75108	Activation, myristolyation of BID and translocation to mitochondria	—
R-HSA-109581	Apoptosis	—
R-HSA-111465	Apoptotic cleavage of cellular proteins	—
R-HSA-75153	Apoptotic execution phase	—
R-HSA-5621481	C-type lectin receptors (CLRs)	—
R-HSA-5218900	CASP8 activity is inhibited	—
R-HSA-5607764	CLEC7A (Dectin-1) signaling	—
R-HSA-5660668	CLEC7A/inflammasome pathway	—
R-HSA-140534	Caspase activation via Death Receptors in the presence of ligand	—
R-HSA-5357769	Caspase activation via extrinsic apoptotic signalling pathway	—
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins	—
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta	—
R-HSA-73887	Death Receptor Signaling	—
R-HSA-69416	Dimerization of procaspase-8	—
R-HSA-75157	FasL/ CD95L signaling	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-446652	Interleukin-1 family signaling	—
R-HSA-9020702	Interleukin-1 signaling	—
R-HSA-109606	Intrinsic Pathway for Apoptosis	—
R-HSA-975871	MyD88 cascade initiated on plasma membrane	—
R-HSA-975155	MyD88 dependent cascade initiated on endosome	—
R-HSA-166166	MyD88-independent TLR4 cascade	—
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane	—
R-HSA-933543	NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	—
R-HSA-168638	NOD1/2 Signaling Pathway	—
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	—
R-HSA-5357801	Programmed Cell Death	—
R-HSA-5213460	RIPK1-mediated regulated necrosis	—
R-HSA-5218859	Regulated Necrosis	—
R-HSA-3371378	Regulation by c-FLIP	—
R-HSA-9758274	Regulation of NF-kappa B signaling	—
R-HSA-5357905	Regulation of TNFR1 signaling	—
R-HSA-5675482	Regulation of necroptotic cell death	—
R-HSA-162582	Signal Transduction	—
R-HSA-449147	Signaling by Interleukins	—
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation	—
R-HSA-9013957	TLR3-mediated TICAM1-dependent programmed cell death	—
R-HSA-75893	TNF signaling	—
R-HSA-5357786	TNFR1-induced proapoptotic signaling	—
R-HSA-975138	TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	—
R-HSA-75158	TRAIL signaling	—
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling	—
R-HSA-2562578	TRIF-mediated programmed cell death	—
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade	—
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade	—
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade	—
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade	—
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade	—
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade	—
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade	—
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade	—
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade	—
R-HSA-168898	Toll-like Receptor Cascades	—

MSigDB gene sets: 560 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE45365_NK_CELL_VS_BCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RESPONSE_TO_ETHANOL, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_RESPONSE_TO_ESTRADIOL, GNF2_CASP8, REACTOME_NOD1_2_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM

GO Biological Process (46): angiogenesis (GO:0001525), regulation of cytokine production (GO:0001817), proteolysis (GO:0006508), apoptotic process (GO:0006915), heart development (GO:0007507), extrinsic apoptotic signaling pathway via death domain receptors (GO:0008625), regulation of tumor necrosis factor-mediated signaling pathway (GO:0010803), protein processing (GO:0016485), natural killer cell activation (GO:0030101), macrophage differentiation (GO:0030225), positive regulation of cell migration (GO:0030335), response to cobalt ion (GO:0032025), response to estradiol (GO:0032355), response to lipopolysaccharide (GO:0032496), positive regulation of interleukin-1 beta production (GO:0032731), response to tumor necrosis factor (GO:0034612), TRAIL-activated apoptotic signaling pathway (GO:0036462), T cell activation (GO:0042110), B cell activation (GO:0042113), positive regulation of apoptotic process (GO:0043065), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), positive regulation of neuron apoptotic process (GO:0043525), regulation of innate immune response (GO:0045088), response to ethanol (GO:0045471), positive regulation of macrophage differentiation (GO:0045651), positive regulation of proteolysis (GO:0045862), protein maturation (GO:0051604), negative regulation of necroptotic process (GO:0060546), syncytiotrophoblast cell differentiation involved in labyrinthine layer development (GO:0060715), pyroptotic inflammatory response (GO:0070269), cellular response to mechanical stimulus (GO:0071260), response to anesthetic (GO:0072347), apoptotic signaling pathway (GO:0097190), extrinsic apoptotic signaling pathway (GO:0097191), execution phase of apoptosis (GO:0097194), self proteolysis (GO:0097264), positive regulation of execution phase of apoptosis (GO:1900119), regulation of immune system process (GO:0002682), positive regulation of signal transduction (GO:0009967), cell differentiation (GO:0030154), protein catabolic process (GO:0030163), regulation of apoptotic process (GO:0042981), chordate embryonic development (GO:0043009), animal organ development (GO:0048513), death-inducing signaling complex assembly (GO:0071550)

GO Molecular Function (14): cysteine-type endopeptidase activity (GO:0004197), death receptor binding (GO:0005123), tumor necrosis factor receptor binding (GO:0005164), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), ubiquitin protein ligase binding (GO:0031625), death effector domain binding (GO:0035877), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), scaffold protein binding (GO:0097110), endopeptidase activity (GO:0004175), protein binding (GO:0005515), cysteine-type endopeptidase activator activity involved in apoptotic process (GO:0008656), hydrolase activity (GO:0016787)

GO Cellular Component (14): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), cytosol (GO:0005829), cytoskeleton (GO:0005856), lamellipodium (GO:0030027), death-inducing signaling complex (GO:0031264), CD95 death-inducing signaling complex (GO:0031265), protein-containing complex (GO:0032991), cell body (GO:0044297), ripoptosome (GO:0097342), plasma membrane (GO:0005886), Noc1p-Noc2p complex (GO:0030690)

Reactome top-level categories

17 top-level categories:

Category	Pathways
Caspase activation via Death Receptors in the presence of ligand	2
TNF signaling	2
Death Receptor Signaling	2
Apoptotic execution phase	1
Caspase activation via extrinsic apoptotic signalling pathway	1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
TRIF (TICAM1)-mediated TLR4 signaling	1
Apoptotic cleavage of cellular proteins	1
Regulated Necrosis	1
Regulation of necroptotic cell death	1
CLEC7A (Dectin-1) signaling	1
RIPK1-mediated regulated necrosis	1
Intrinsic Pathway for Apoptosis	1
Apoptosis	1
Toll Like Receptor 3 (TLR3) Cascade	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
Defective RIPK1-mediated regulated necrosis	1

GO top-level categories

showing 60 of 66 GO namespaces:

Category	Terms
lymphocyte activation	3
cellular anatomical structure	3
response to lipid	2
response to oxygen-containing compound	2
tumor necrosis factor receptor superfamily binding	2
peptidase activity	2
protein binding	2
binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cytokine production	1
regulation of gene expression	1
regulation of multicellular organismal process	1
protein metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
animal organ development	1
circulatory system development	1
extrinsic apoptotic signaling pathway	1
regulation of cytokine-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
proteolysis	1
protein maturation	1
myeloid leukocyte differentiation	1
mononuclear cell differentiation	1
cell migration	1
regulation of cell migration	1
positive regulation of cell motility	1
response to metal ion	1
response to molecule of bacterial origin	1
interleukin-1 beta production	1
regulation of interleukin-1 beta production	1
positive regulation of interleukin-1 production	1
response to cytokine	1
extrinsic apoptotic signaling pathway via death domain receptors	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
endopeptidase activity	1
cysteine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
ubiquitin-like protein ligase binding	1
protein domain specific binding	1
peptidase activator activity involved in apoptotic process	1
cysteine-type endopeptidase regulator activity involved in apoptotic process	1
catalytic activity	1
intracellular anatomical structure	1
mitochondrial membrane	1
organelle outer membrane	1
intracellular membraneless organelle	1
cell leading edge	1
plasma membrane bounded cell projection	1
plasma membrane protein complex	1
death-inducing signaling complex	1
cellular_component	1
cytosol	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 31 of 75 annotations. The rest are phylogenetic / computational / electronic (IEA).

31 experimentally-supported GO terms:

GO term	NS	Evidence
TRAIL-activated apoptotic signaling pathway	BP	direct assay
apoptotic process	BP	mutant phenotype
apoptotic signaling pathway	BP	mutant phenotype
cellular response to mechanical stimulus	BP	expression pattern
execution phase of apoptosis	BP	mutant phenotype
extrinsic apoptotic signaling pathway	BP	direct assay
extrinsic apoptotic signaling pathway via death domain receptors	BP	direct assay
negative regulation of canonical NF-kappaB signal transduction	BP	mutant phenotype
negative regulation of necroptotic process	BP	direct assay
positive regulation of canonical NF-kappaB signal transduction	BP	mutant phenotype
positive regulation of cell migration	BP	direct assay
positive regulation of execution phase of apoptosis	BP	direct assay
positive regulation of interleukin-1 beta production	BP	mutant phenotype
positive regulation of macrophage differentiation	BP	mutant phenotype
positive regulation of proteolysis	BP	direct assay
protein maturation	BP	direct assay
proteolysis	BP	direct assay
response to tumor necrosis factor	BP	mutant phenotype
CD95 death-inducing signaling complex	CC	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
death-inducing signaling complex	CC	direct assay
lamellipodium	CC	direct assay
protein-containing complex	CC	direct assay
ripoptosome	CC	direct assay
cysteine-type endopeptidase activity	MF	direct assay
death effector domain binding	MF	physical interaction
identical protein binding	MF	physical interaction
peptidase activity	MF	direct assay
scaffold protein binding	MF	physical interaction
ubiquitin protein ligase binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 3,666 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP8	FADD	Q13158	976
CASP8	FASLG	P48023	948
CASP8	CYCS	P00001	943
CASP8	BCL2	P10415	943
CASP8	BAX	P55269	918
CASP8	TNFRSF10B	O14763	914
CASP8	FAS	P25445	894
CASP8	CASP3	P42574	890
CASP8	CFLAR	O15519	890
CASP8	APAF1	O14727	873
CASP8	TNFRSF10A	O00220	872
CASP8	TNF	P01375	866
CASP8	RIPK1	Q13546	861
CASP8	TNFRSF1A	P19438	860
CASP8	TP53	P04637	858

IntAct

Human interaction partners of CASP8 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 100 partners by confidence:

Partner	Interaction type	MIscore	Records
FADD	association	0.980	29
RIPK1	association	0.960	8
FAS	colocalization	0.920	7
TNFSF10	colocalization	0.920	1
TNFRSF10A	association	0.820	6
FASLG	association	0.800	3
TNFRSF10B	association	0.750	2
CFLAR	association	0.740	9
CASP10	direct interaction	0.730	4
CASP8AP2	physical association	0.700	5
CUL3	physical association	0.600	5
BCAP31	physical association	0.590	3
APP	physical association	0.560	3
FMR1	physical association	0.560	3
PLK1	physical association	0.560	3
RAF1	physical association	0.560	3
UNG	physical association	0.560	3
VPS33A	physical association	0.560	3
ANGPTL4	physical association	0.550	1
NOL3	physical association	0.520	3
PTPN6	physical association	0.520	3
RNF34	physical association	0.510	3
MALT1	association	0.500	5
TNFAIP3	association	0.500	3
CASP3	direct interaction	0.440	1
NMT1	protein cleavage	0.440	1
NUCB1	cleavage reaction	0.440	1
NUCB2	cleavage reaction	0.440	1
P35	direct interaction	0.440	1
PARP10	cleavage reaction	0.440	1

BioGRID (493 interactions; top human partners by supporting records): FADD (Reconstituted Complex; 52 records), RIPK1 (Affinity Capture-Western; 46 records), CFLAR (Biochemical Activity; 29 records), TNFRSF10B (Affinity Capture-MS; 16 records), FAS (Affinity Capture-MS; 14 records), TNFRSF10A (Affinity Capture-Western; 14 records), CASP10 (Affinity Capture-Western; 10 records), TRAF6 (Affinity Capture-Western; 10 records), TNFSF10 (Affinity Capture-Western; 8 records), TRAF2 (Affinity Capture-Western; 8 records), BCAP31 (Reconstituted Complex; 7 records), TNFAIP3 (Affinity Capture-Western; 6 records), CUL3 (Affinity Capture-Western; 5 records), SQSTM1 (Affinity Capture-Western; 5 records), SRC (Affinity Capture-Western; 5 records)

SIGNOR signaling

showing 37 of 47 signaling interactions:

A	Effect	B	Mechanism
RIPK1	“up-regulates activity”	CASP8	binding
CASP6	up-regulates	CASP8	cleavage
FADD	“up-regulates activity”	CASP8	binding
BFAR	down-regulates	CASP8	binding
TRADD	“up-regulates activity”	CASP8	binding
MAPK14	down-regulates	CASP8	phosphorylation
MAVS	up-regulates	CASP8	relocalization
SRC	down-regulates	CASP8	phosphorylation
CASP8	“up-regulates activity”	CASP3	cleavage
CASP8	up-regulates	CASP8AP2	binding
CASP8	up-regulates	CASP7	cleavage
CDK1	down-regulates	CASP8	phosphorylation
MAPK1	down-regulates	CASP8	phosphorylation
MAPK3	down-regulates	CASP8	phosphorylation
CyclinB/CDK1	down-regulates	CASP8	phosphorylation
ERK1/2	down-regulates	CASP8	phosphorylation
PTPN6	“up-regulates activity”	CASP8	dephosphorylation
“Caspase 6 complex”	up-regulates	CASP8	cleavage
CASP8	up-regulates	Cell_death
M	“up-regulates activity”	CASP8
Gbeta	down-regulates	CASP8	phosphorylation
HECTD3	“down-regulates activity”	CASP8	polyubiquitination
CASP8	“down-regulates activity”	RNF31	cleavage
CASP8	“up-regulates activity”	BID	cleavage
CASP8	up-regulates	CASP6	cleavage
CFLAR	“down-regulates activity”	CASP8	binding
CASP8	“up-regulates activity”	CYCS
CASP8	“down-regulates activity”	RIPK1	cleavage
CASP8	up-regulates	Apoptosis
CASP8	“form complex”	“Caspase 8 complex”	binding
CASP8	“up-regulates activity”	PSEN2	cleavage
CASP8	“up-regulates activity”	PSEN1	cleavage
LYN	“down-regulates activity”	CASP8	phosphorylation
PLK1	“down-regulates quantity by destabilization”	CASP8	phosphorylation
PLK3	“up-regulates activity”	CASP8	phosphorylation
RPS6KA3	“down-regulates quantity by destabilization”	CASP8	phosphorylation
CASP8	“up-regulates activity”	CASP9

Protein complexes (CORUM) (26)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

26 complexes by size:

Complex	Subunits	Members
AIM2 PANoptosome complex	9	PYCARD, AIM2, MEFV, RIPK1, RIPK3, ZBP1, CASP1, CASP8, FADD
PANoptosome	7	CASP8, FADD, NLRP3, PYCARD, RIPK1, RIPK3, ZBP1
TLR3-associated signaling complex	7	CASP8, CFLAR, FADD, RIPK1, TICAM1, TLR3
TLR3 death-signaling complex	7	CFLAR, FADD, RIPK1, TICAM1, TLR3, CASP10, CASP8
Pro-death complex II, cytosolic	6	TRADD, TRAF2, BIRC2, CASP8, FADD, RIPK1
CASP8-CHUK-IKBKB-MALT1-BCL10 complex	5	IKBKB, MALT1, BCL10, CASP8, CHUK
NLRP3-NLRC4 inflammasome	5	CASP1, CASP8, NLRC4, NLRP3, PYCARD
BCL10-CARD9-CASP8-MALT1-PYCARD inflammasome complex	5	MALT1, PYCARD, BCL10, CARD9, CASP8
CASP8-CASP10-FADD-FLIP(S)-RIPK1 complex	5	CASP10, CASP8, CFLAR, FADD, RIPK1
TLR3-DISC complex, atypical	5	TICAM1, TLR3, CASP8, FADD, RIPK1
CASP8-FADD-MALT1-BCL10 complex	4	BCL10, CASP8, FADD, MALT1
DISC complex (FAS, FADD, CASP8, CFLAR), membrane-associated, CD95L induced	4	CASP8, CFLAR, FADD, FAS
CASP8-CASP10-FADD-FAS complex	4	FAS, CASP10, CASP8, FADD
CASP8-FADD-RIPK1-RIPK3 complex	4	CASP8, FADD, RIPK1, RIPK3
★ BCL2-BFAR-CASP8 complex	3	BCL2, BFAR, CASP8
MRIT complex	3	BCL2L1, CASP8, CFLAR
Death induced signaling complex II (CASP8, CFLAR, FADD), cytosolic, CD95L induced	3	CASP8, CFLAR, FADD
DISC complex (FAS, FADD, CASP8)	3	CASP8, FADD, FAS
DISC complex (CD95, FADD, CASP8)	3	CD95, FADD, CASP8
LRRK2-FADD-CASP8 complex	3	FADD, LRRK2, CASP8
AIM2 inflammasome (CASP8)	3	AIM2, CASP8, PYCARD
MALT1-ASC-CASP8 inflammasome	3	CASP8, MALT1, PYCARD
FADDosome complex, TRAIL-R induced	3	CASP8, FADD, RIPK1
SUG1-NLRC4-CASP8 complex	3	CASP8, NLRC4, PSMC5
CASP8-FLIP(L) complex	2	CASP8, CFLAR
★ AR-CASP8 complex	2	AR, CASP8

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 100 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Caspase activation via Death Receptors in the presence of ligand	7	68.3×	4e-10
RIPK1-mediated regulated necrosis	8	46.9×	4e-10
TNFR1-induced NF-kappa-B signaling pathway	7	30.1×	2e-07
TNFR1-induced proapoptotic signaling	5	28.2×	4e-05
Regulation of TNFR1 signaling	9	25.8×	5e-09
Dengue Virus Genome Translation and Replication	5	20.3×	2e-04
Intrinsic Pathway for Apoptosis	5	18.8×	2e-04
Negative regulation of MAPK pathway	5	17.0×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
extrinsic apoptotic signaling pathway via death domain receptors	10	44.1×	1e-11
negative regulation of extrinsic apoptotic signaling pathway via death domain receptors	6	38.3×	2e-06
positive regulation of extrinsic apoptotic signaling pathway	6	30.0×	6e-06
thymus development	6	22.2×	3e-05
tumor necrosis factor-mediated signaling pathway	6	21.8×	3e-05
cellular response to mechanical stimulus	9	21.4×	7e-08
intrinsic apoptotic signaling pathway in response to DNA damage	5	17.8×	5e-04
extrinsic apoptotic signaling pathway	5	16.8×	6e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 11 cancer types — BCC, BLCA, BRCA, CEAD, CESC, CSCC, HNSC, NHL, NPC, STAD, VULVA.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for CASP8: 424 ClinVar records (25 pathogenic / likely pathogenic); 2 CIViC cancer variants; 25 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

424 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	6
Uncertain significance	187
Likely benign	144
Benign	24

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 25 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
631840	NM_001372051.1(CASP8):c.1165C>T (p.Gln389Ter)	Pathogenic	criteria provided, single submitter	1
946113	NM_001372051.1(CASP8):c.202C>T (p.Arg68Ter)	Pathogenic	criteria provided, single submitter	1
968654	NM_001372051.1(CASP8):c.306-1949_306-1947delinsC	Pathogenic	criteria provided, single submitter	1
1394714	NM_001372051.1(CASP8):c.879T>A (p.Tyr293Ter)	Pathogenic	criteria provided, single submitter	1
1935186	NM_001372051.1(CASP8):c.306-1930dup	Pathogenic	criteria provided, single submitter	1
2037856	NM_001372051.1(CASP8):c.679C>T (p.Gln227Ter)	Pathogenic	criteria provided, single submitter	1
2072614	NM_001372051.1(CASP8):c.306-1954_306-1953del	Pathogenic	criteria provided, single submitter	1
2130976	NM_001372051.1(CASP8):c.429_430insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGGAAGCTCCCAAGATGACTACCTCCAGCCTCTGGCCACAGGGAACCTTCTTCATATCCCACAAGCAAAGGAGCTGGATATTTTC (p.Phe143_Ile144insPhePhePhePhePhePheXaaXaaXaaXaaGlySerSerGlnAspAspTyrLeuGlnProLeuAlaThrGlyAsnLeuLeuHisIleProGlnAlaLysGluLeuAspIlePhe)	Pathogenic	criteria provided, single submitter	1
2186059	NM_001372051.1(CASP8):c.983dup (p.Gln329fs)	Pathogenic	criteria provided, single submitter	1
2762094	NM_001372051.1(CASP8):c.492_493del (p.Ala165fs)	Pathogenic	criteria provided, single submitter	1
2790366	NM_001372051.1(CASP8):c.306-1976del	Pathogenic	criteria provided, single submitter	1
2885998	NM_001372051.1(CASP8):c.306-1978G>T	Pathogenic	criteria provided, single submitter	1
2896117	NM_001372051.1(CASP8):c.918del (p.Asn306fs)	Pathogenic	criteria provided, single submitter	1
4812021	NM_001372051.1(CASP8):c.613dup (p.Val205fs)	Pathogenic	criteria provided, single submitter	1
4847516	NM_001372051.1(CASP8):c.691A>T (p.Lys231Ter)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CASP8’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 999):

Position(s)	Effect	Δscore	Sites
2:201266653	donor_gain	1.0000
2:201284814–201284815	acceptor_loss	1.0000	4
2:201260614–201260615	donor_loss	0.9900	2
2:201266482	acceptor_gain	0.9900
2:201266768	donor_gain	0.9900
2:201272636–201272637	acceptor_loss	0.9900	6
2:201284808	acceptor_gain	0.9900
2:201284815	acceptor_loss	0.9900	2
2:201260614–201260615	donor_loss	0.9800	3
2:201271513–201271515	acceptor_loss	0.9800	7

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Bladder Urothelial Carcinoma (TCGA)	favorable	5.84e-05
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.000548

Disease associations

OMIM: gene MIM:601763 | disease phenotypes: MIM:607271, MIM:114550

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
autoimmune lymphoproliferative syndrome type 2B	Strong	Autosomal recessive	3

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
autoimmune lymphoproliferative syndrome type 2B	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (2 panels, 2 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

2 panels:

Panel	Rating
COVID-19 research	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green

Mondo (2): autoimmune lymphoproliferative syndrome type 2B (MONDO:0011804), hepatocellular carcinoma (MONDO:0007256)

Orphanet (2): Autoimmune lymphoproliferative syndrome-recurrent viral infections due to CASP8 deficiency (Orphanet:275517), Hepatocellular carcinoma (Orphanet:88673)

HPO phenotypes

28 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000964	Eczematoid dermatitis
HP:0001402	Hepatocellular carcinoma
HP:0001413	Micronodular cirrhosis
HP:0001442	Typified by somatic mosaicism
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0002028	Chronic diarrhea
HP:0002090	Pneumonia
HP:0002099	Asthma
HP:0002716	Lymphadenopathy
HP:0002720	Decreased circulating IgA concentration
HP:0002850	Decreased circulating IgM concentration
HP:0003002	Breast carcinoma
HP:0004315	Decreased circulating IgG concentration
HP:0004322	Short stature
HP:0005353	Recurrent herpes
HP:0005384	Defective B cell activation
HP:0005419	Decreased T cell activation
HP:0005425	Recurrent sinopulmonary infections
HP:0006519	Alveolar cell carcinoma
HP:0006572	Subacute progressive viral hepatitis
HP:0030078	Lung adenocarcinoma
HP:0030358	Non-small cell lung carcinoma
HP:0033222	Inverted CD4:CD8 ratio
HP:0033278	Reduced CD95-induced lymphocyte apoptosis
HP:0410300	Complete or near-complete absence of specific antibody response to unconjugated pneumococcus polysaccharide

GWAS associations

25 associations:

Study	Trait	p-value
GCST90013410_35	Basal cell carcinoma	7e-47
GCST90002400_23	Plateletcrit	8e-27
GCST004627_176	Lymphocyte count	2e-19
GCST004113_1	Basal cell carcinoma	4e-18
GCST004988_316	Breast cancer	2e-16
GCST90002399_209	Neutrophil percentage of white cells	6e-16
GCST90002407_274	White blood cell count	4e-15
GCST002568_7	Esophageal squamous cell carcinoma	4e-13
GCST010304_76	Cutaneous malignant melanoma	2e-12
GCST010303_41	Nevus count or cutaneous melanoma	3e-12
GCST004146_3	Chronic lymphocytic leukemia	5e-11
GCST001267_3	Melanoma	9e-10
GCST004142_2	Melanoma	9e-10
GCST002318_121	Rheumatoid arthritis	2e-9
GCST002842_11	Basal cell carcinoma	2e-9
GCST002073_6	Chronic lymphocytic leukemia	3e-9
GCST002318_13	Rheumatoid arthritis	3e-9
GCST90016667_20	Spleen volume	3e-9
GCST006085_90	Prostate cancer	2e-8
GCST003468_3	Chronic lymphocytic leukemia	3e-8
GCST008834_23	Non-small cell lung cancer	4e-8
GCST006959_95	Rheumatoid arthritis	3e-7
GCST006959_13	Rheumatoid arthritis	5e-7
GCST009597_261	Multiple sclerosis	1e-6
GCST007505_29	Nevus count or cutaneous melanoma	4e-6

EFO canonical traits (from GWAS)

4 canonical traits:

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0004632	nevus count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007985	platelet crit

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
D006528	Carcinoma, Hepatocellular	C04.557.470.200.025.255; C04.588.274.623.160; C06.301.623.160; C06.552.697.160

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3776 (SINGLE PROTEIN), CHEMBL3831289 (PROTEIN FAMILY)

Drugs by curated mechanism of action (ChEMBL)

Drugs whose curated ChEMBL mechanism of action targets the CASP8 protein itself — single-protein targets only (drugs acting on a protein family or complex that merely includes it are excluded). Includes antibodies and oligonucleotides that bioactivity screening does not capture.

1 curated-mechanism drugs:

Drug	Modality	Max phase
NIVOCASAN	Small molecule	2

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 3,460 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL43128	PRIMAQUINE PHOSPHATE	4	2,039
CHEMBL437526	PRALNACASAN	2	1,421

Clinical evidence (CIViC)

Drug × variant × indication, from 1 curated evidence items; also 1 prognostic. CIViC evidence level: A (validated) → B (clinical) → C (case study) → D (preclinical) → E (inferential).

1 predictive associations by evidence level:

Variant	Therapy	Indication	Effect	Level	CIViC
CASP8 Overexpression	Conatumumab	Ewing Sarcoma Of Bone	Sensitivity/Response	CIViC D	EID831

CIViC curated variants (2)

Named clinical variants curated in CIViC for this gene (the catalogue beneath the predictive evidence above):

Overexpression, D302H (missense variant,polymorphic sequence variant).

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

4 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs6736233		Efficacy	Allele G is associated with increased likelihood of Recurrence in children with Acute lymphoblastic leukemia as compared to allele C.	PMID:39733427
rs1045487	HMG-CoA reductase inhibitors	Toxicity	Genotype GG is associated with increased likelihood of Toxic liver disease when treated with HMG-CoA reductase inhibitors as compared to genotypes AA + AG.	PMID:42044984
rs3769825	HMG-CoA reductase inhibitors	Toxicity	Genotypes AG + GG is associated with increased likelihood of Toxic liver disease when treated with HMG-CoA reductase inhibitors as compared to genotype AA.	PMID:42044984
rs6745051	HMG-CoA reductase inhibitors	Toxicity	Genotype CC is associated with increased likelihood of Toxic liver disease when treated with HMG-CoA reductase inhibitors as compared to genotypes AA + AC.	PMID:42044984

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — C14: Caspase

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
emricasan	Inhibition	8.3	pKi
compound 4 [PMID: 12408711]	Inhibition	6.06	pKi

Binding affinities (BindingDB)

322 measured of 437 human assays (440 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
(S)-5-[(1,3-Dihydro-isoindol-2-ylmethyl)-amino]-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.0087 nM
(S)-5-[(3,4-Dihydro-1H-isoquinolin-2-ylmethyl)-amino]-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.013 nM
(S)-3-(2-{5-Ethyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-5-{[(hexyl-methyl-amino)-methyl]-amino}-4-oxo-pentanoic acid	IC50	0.025 nM
(S)-3-(2-{3-[(4-Methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-5-{[(methyl-octyl-amino)-methyl]-amino}-4-oxo-pentanoic acid	IC50	0.025 nM
(S)-5-{[(Hexyl-methyl-amino)-methyl]-amino}-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.028 nM
(S)-5-{[(Butyl-methyl-amino)-methyl]-amino}-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.031 nM
(S)-5-[(4-Benzyl-piperidin-1-ylmethyl)-amino]-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.047 nM
(S)-3-(2-{3-[(4-Methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-5-{[(methyl-pentyl-amino)-methyl]-amino}-4-oxo-pentanoic acid	IC50	0.048 nM
[3-(2-{5-tert-Butyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-carboxy-2-oxo-butyl]-hexyl-methyl-ammonium; chloride	IC50	0.05 nM
(S)-5-{[(Ethyl-methyl-amino)-methyl]-amino}-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.056 nM
(S)-3-{(S)-2-[3-((S)-2-Acetylamino-3-carboxy-propionylamino)-2-oxo-2H-pyridin-1-yl]-butyrylamino}-5-benzylsulfanyl-4-oxo-pentanoic acid	IC50	0.06 nM
(S)-5-{[(Hexyl-methyl-amino)-methyl]-amino}-3-(2-{5-isopropyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.063 nM
(S)-3-(2-{3-[(4-Methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-5-((S)-1-phenyl-ethylamino)-pentanoic acid	IC50	0.064 nM
(S)-5-Benzylsulfanyl-4-oxo-3-(2-{2-oxo-3-[(thiophen-2-ylmethyl)-amino]-2H-pyrazin-1-yl}-butyrylamino)-pentanoic acid	IC50	0.065 nM
(S)-3-(2-{5-tert-Butyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-5-{[(hexyl-methyl-amino)-methyl]-amino}-4-oxo-pentanoic acid	IC50	0.067 nM
(S)-5-Benzylsulfanyl-3-(2-{3-[(2,3-dihydro-benzo[1,4]dioxin-2-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.087 nM
[3-(2-{5-tert-Butyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-carboxy-2-oxo-butyl]-methyl-pentyl-ammonium; chloride	IC50	0.11 nM
(S)-3-(2-{5-(1-Ethyl-1-methyl-propyl)-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-5-{[(hexyl-methyl-amino)-methyl]-amino}-4-oxo-pentanoic acid	IC50	0.11 nM
(S)-3-(2-{5-tert-Butyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-5-{[(methyl-pentyl-amino)-methyl]-amino}-4-oxo-pentanoic acid	IC50	0.11 nM
(S)-5-Benzylsulfanyl-4-oxo-3-(2-{2-oxo-3-[(thiazol-2-ylmethyl)-amino]-2H-pyrazin-1-yl}-butyrylamino)-pentanoic acid	IC50	0.13 nM
(S)-3-(2-{3-[(4-Methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-butyric acid	IC50	0.15 nM
(S)-5-Benzylsulfanyl-4-oxo-3-(2-{2-oxo-3-[(thiazol-5-ylmethyl)-amino]-2H-pyrazin-1-yl}-butyrylamino)-pentanoic acid	IC50	0.19 nM
(S)-5-Benzylsulfanyl-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.22 nM
(S)-5-Benzylsulfanyl-3-{2-[3-(2-methyl-benzothiazol-5-ylamino)-2-oxo-2H-pyrazin-1-yl]-butyrylamino}-4-oxo-pentanoic acid	IC50	0.22 nM
(S)-5-Benzylsulfanyl-3-(2-{3-[(3-methyl-isoxazol-5-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.23 nM
(S)-3-(2-{3-[(4-Methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-5-[(pyrrolidin-1-ylmethyl)-amino]-pentanoic acid	IC50	0.29 nM
(3S)-3-[(2S)-2-[(4S)-4-[(3S)-3-acetamido-3-formamidopropanoic acid]-4-formamidobutanoic acid]-3-methylbutanamido]-4-oxo-7-phenylheptanoic acid	IC50	0.31 nM
(S)-5-Benzylsulfanyl-3-(2-{3-[(isoxazol-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.4 nM
(S)-3-(2-{3-[(4-Methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-4-(5-phenyl-oxazol-2-yl)-butyric acid	IC50	0.46 nM
(S)-3-(2-{5-tert-Butyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-5-[(piperidin-1-ylmethyl)-amino]-pentanoic acid	IC50	0.62 nM
(S)-3-(2-{3-[(4-Methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-5-{[(methyl-propyl-amino)-methyl]-amino}-4-oxo-pentanoic acid	IC50	0.62 nM
(S)-5-Benzylsulfanyl-3-(2-{3-[(3-methyl-[1,2,4]oxadiazol-5-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.67 nM
(S)-3-(2-{5-tert-Butyl-3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-5-[(morpholin-4-ylmethyl)-amino]-4-oxo-pentanoic acid	IC50	0.73 nM
(S)-5-[(7-Aza-bicyclo[2.2.1]hept-7-ylmethyl)-amino]-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.88 nM
(S)-5-(Dimethylaminomethyl-amino)-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.89 nM
(S)-5-Benzylsulfanyl-3-(2-{3-[2-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.9 nM
(S)-5-Benzylsulfanyl-3-{2-[3-(3-methoxy-propylamino)-2-oxo-2H-pyrazin-1-yl]-butyrylamino}-4-oxo-pentanoic acid	IC50	0.92 nM
(S)-5-Benzylsulfanyl-4-oxo-3-(2-{2-oxo-3-[(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-amino]-2H-pyrazin-1-yl}-butyrylamino)-pentanoic acid	IC50	0.98 nM
(S)-5-Benzylsulfanyl-4-oxo-3-{2-[2-oxo-3-(2-pyrazol-1-yl-ethylamino)-2H-pyrazin-1-yl]-butyrylamino}-pentanoic acid	IC50	0.99 nM
(4S,7S,11aS)-benzyl 4-(((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)carbamoyl)-7-(2-naphthamido)-6-oxo-3,4,7,8,11,11a-hexahydro-1H-pyrazino[1,2-a]azocine-2(6H)-carboxylate	IC50	1 nM
(4S,7S,11aS)-N-((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)-7-(isoquinoline-1-carboxamido)-6-oxo-2-(phenylsulfonyl)-decahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	IC50	1 nM
(4S,7S,11aS)-N-((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)-7-(isoquinoline-1-carboxamido)-6-oxo-decahydro-[1,4]oxazino[4,3-a]azocine-4-carboxamide	IC50	1 nM
(4S,7S,11aS)-benzyl 4-(((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)carbamoyl)-7-benzamido-6-oxo-3,4,7,8,11,11a-hexahydro-1H-pyrazino[1,2-a]azocine-2(6H)-carboxylate	IC50	1 nM
(4S,7S,11aS)-N-((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)-7-(isoquinoline-1-carboxamido)-6-oxo-decahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	IC50	1 nM
(4S,7S,11aS)-7-(2-naphthamido)-N-((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)-6-oxo-decahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	IC50	1 nM
(4S,7S,11aS)-benzyl 4-(((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)carbamoyl)-7-(isoquinoline-1-carboxamido)-6-oxo-3,4,7,8,11,11a-hexahydro-1H-pyrazino[1,2-a]azocine-2(6H)-carboxylate	IC50	1 nM
(4S,7S,11aS)-7-(benzo[b]thiophene-2-carboxamido)-N-((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)-6-oxo-decahydro-[1,4]oxazino[4,3-a]azocine-4-carboxamide	IC50	1 nM
(4S,7S,11aS)-7-(2-naphthamido)-N-((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)-6-oxo-decahydro-[1,4]oxazino[4,3-a]azocine-4-carboxamide	IC50	1 nM
(4S,7S,11aS)-7-(2-naphthamido)-N-((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)-2-(methylsulfonyl)-6-oxo-decahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	IC50	1 nM
(4S,7S,11aS)-N-((3S)-2-hydroxy-5-oxo-tetrahydrofuran-3-yl)-7-(isoquinoline-1-carboxamido)-2-(methylsulfonyl)-6-oxo-decahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	IC50	1 nM

ChEMBL bioactivities

346 potent at pChembl≥5 of 414 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.92	IC50	0.12	nM	CHEMBL5569363
9.04	Ki	0.92	nM	CHEMBL5723373
9.00	IC50	1	nM	CHEMBL5822466
8.89	Ki	1.3	nM	CHEMBL3934331
8.89	Ki	1.3	nM	CHEMBL91281
8.80	Ki	1.6	nM	CHEMBL5723323
8.72	Ki	1.9	nM	CHEMBL315868
8.68	Ki	2.1	nM	CHEMBL194207
8.60	Ki	2.5	nM	CHEMBL3914770
8.59	Ki	2.6	nM	CHEMBL3917557
8.52	Ki	3	nM	CHEMBL93960
8.52	Ki	3	nM	CHEMBL90589
8.48	IC50	3.3	nM	CHEMBL5715925
8.47	Ki	3.4	nM	CHEMBL327821
8.44	Ki	3.6	nM	CHEMBL3983217
8.43	Ki	3.7	nM	CHEMBL88540
8.42	IC50	3.82	nM	CHEMBL5715921
8.40	IC50	4	nM	CHEMBL199492
8.40	Ki	4	nM	CHEMBL91423
8.40	Ki	4	nM	CHEMBL3977587
8.40	Ki	4	nM	CHEMBL3944828
8.40	Ki	4	nM	CHEMBL330110
8.40	Ki	4	nM	CHEMBL314096
8.40	IC50	4	nM	CHEMBL5715934
8.39	Ki	4.1	nM	CHEMBL3909635
8.38	Ki	4.2	nM	CHEMBL3961549
8.38	IC50	4.2	nM	CHEMBL478695
8.36	Ki	4.4	nM	CHEMBL3960740
8.34	Ki	4.6	nM	CHEMBL382967
8.33	Ki	4.7	nM	CHEMBL1199647
8.30	IC50	5	nM	CHEMBL372189
8.30	Ki	5	nM	CHEMBL90914
8.30	Ki	5	nM	CHEMBL315954
8.30	Ki	5	nM	CHEMBL327207
8.30	IC50	5	nM	CHEMBL5715934
8.28	Ki	5.3	nM	CHEMBL430839
8.28	Ki	5.2	nM	CHEMBL330534
8.27	Ki	5.4	nM	CHEMBL88795
8.26	Ki	5.5	nM	CHEMBL3927125
8.26	Ki	5.5	nM	CHEMBL372185
8.24	Ki	5.7	nM	CHEMBL3906503
8.24	Ki	5.8	nM	CHEMBL3913186
8.22	IC50	6	nM	CHEMBL185356
8.22	Ki	6	nM	CHEMBL90185
8.22	IC50	6	nM	CHEMBL237310
8.15	IC50	7	nM	CHEMBL90224
8.15	IC50	7	nM	CHEMBL23226
8.13	Ki	7.4	nM	CHEMBL3981787
8.12	IC50	7.6	nM	CHEMBL322631
8.10	Ki	8	nM	CHEMBL3930460

PubChem BioAssay actives

302 with measured affinity, of 924 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4S,7S)-N-[(2R,3S)-2-hydroxy-5-oxooxolan-3-yl]-7-(isoquinoline-1-carbonylamino)-6,10-dioxo-2,3,4,7,8,9-hexahydro-1H-pyridazino[1,2-a]diazepine-4-carboxamide	2100626: Inhibition of caspase-8 (unknown origin) by fluorescence based analysis	ic50	0.0001	uM
benzyl (4S,7S,9Z,11aS)-4-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-7-(isoquinoline-1-carbonylamino)-6-oxo-3,4,7,8,11,11a-hexahydro-1H-pyrazino[1,2-a]azocine-2-carboxylate	257629: Inhibitory activity against Caspase 8	ic50	0.0040	uM
(4S)-4-[[(2S,3S)-2-acetamido-3-methylpentanoyl]amino]-5-[[(2S,3R)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	415380: Inhibition of human recombinant caspase 8 assessed as accumulation of fluorogenic product by fluorometric assay	ic50	0.0042	uM
(4S)-4-[[(2S)-2-acetamido-3-methylpentanoyl]amino]-5-[[(2S)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.0042	uM
benzyl (4S,7S,9Z,11aS)-4-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-7-(naphthalene-2-carbonylamino)-6-oxo-3,4,7,8,11,11a-hexahydro-1H-pyrazino[1,2-a]azocine-2-carboxylate	257629: Inhibitory activity against Caspase 8	ic50	0.0050	uM
3-[[(2S)-2-[(2,4-dichlorophenyl)methoxycarbonylamino]-3-methylbutanoyl]amino]-5-fluoro-4-oxopentanoic acid	240704: Inhibition concentration required against caspase-8	ic50	0.0060	uM
4-fluoro-2-[[2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]benzoyl]amino]-3-oxobutanoic acid	302017: Inhibition of human caspase 8	ic50	0.0060	uM
5-fluoro-3-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-4-oxopentanoic acid	49707: Compound was evaluated for its inhibitory activity against the Caspase-8 enzyme	ic50	0.0070	uM
(3S)-3-[[(2S)-4-methyl-2-[[2-(naphthalen-1-ylamino)acetyl]amino]pentanoyl]amino]-4-oxobutanoic acid	49706: Binding affinity towards human Caspase-8	ic50	0.0070	uM
N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-[[2-(naphthalen-1-ylamino)acetyl]amino]pentanamide	49719: Inhibition of Caspase-8 enzyme	ic50	0.0076	uM
(4R)-5-[[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-naphthalen-1-yloxy-5-oxopentanoic acid	49719: Inhibition of Caspase-8 enzyme	ic50	0.0120	uM
benzyl (4S,7S,9Z,11aS)-7-benzamido-4-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-6-oxo-3,4,7,8,11,11a-hexahydro-1H-pyrazino[1,2-a]azocine-2-carboxylate	257629: Inhibitory activity against Caspase 8	ic50	0.0130	uM
(3S)-3-[2-[5-tert-butyl-2-oxo-3-(2H-tetrazol-5-ylamino)pyrazin-1-yl]butanoylamino]-4-oxo-7-phenylheptanoic acid	306146: Inhibition of human recombinant caspase 8	ic50	0.0140	uM
N-(4-methoxyphenyl)-N-methyl-1,2,3-benzotriazin-4-amine	1393168: Activation of caspase cascade in human T47D cells using N-(Ac-DEVD)-N’-ethoxycarbonyl-R110 fluorogenic substrate incubated for 48 hrs by fluorescent plate reader based assay	ec50	0.0160	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylbutanoyl]amino]-4-oxo-7-phenylheptanoic acid	241559: Inhibitory concentration against recombinant human caspase-8 in neuronal precursor (NT2) cells	ic50	0.0160	uM
5-fluoro-3-[[(2S)-3-methyl-2-(phenylcarbamoyloxy)butanoyl]amino]-4-oxopentanoic acid	240592: Inhibitory concentration against Caspase-8	ic50	0.0170	uM
(2S)-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-[2-(naphthalen-1-ylamino)propanoylamino]pentanamide	49719: Inhibition of Caspase-8 enzyme	ic50	0.0170	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-4-oxo-9-phenylnonanoic acid	2100634: Binding affinity to Caspase-8 (unknown origin) using Ac-IETD-AFC as substrate assessed as inhibition constant	ki	0.0185	uM
(4S)-5-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-(phenylmethoxycarbonylamino)pentanoic acid	49718: Inhibitory concentration of compound required against Caspase-8 compared to acylated dipeptides	ic50	0.0300	uM
(4S)-5-[[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-naphthalen-1-yloxy-5-oxopentanoic acid	49719: Inhibition of Caspase-8 enzyme	ic50	0.0310	uM
(4S,7S,11aS)-7-benzamido-2-benzoyl-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-6-oxo-3,4,7,8,9,10,11,11a-octahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	257629: Inhibitory activity against Caspase 8	ic50	0.0380	uM
(4S,7S)-N-[(2R,3S)-2-ethoxy-5-oxooxolan-3-yl]-7-(isoquinoline-1-carbonylamino)-6,10-dioxo-2,3,4,7,8,9-hexahydro-1H-pyridazino[1,2-a]diazepine-4-carboxamide	269767: Inhibition of caspase8	ic50	0.0400	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]-4-oxo-8-phenyloctanoic acid	2100634: Binding affinity to Caspase-8 (unknown origin) using Ac-IETD-AFC as substrate assessed as inhibition constant	ki	0.0420	uM
1-[2-[[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-2-oxoethoxy]naphthalene-2-carboxylic acid	49719: Inhibition of Caspase-8 enzyme	ic50	0.0480	uM
(4S,7S,11aS)-2-(benzenesulfonyl)-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-7-(naphthalene-2-carbonylamino)-6-oxo-3,4,7,8,9,10,11,11a-octahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	257629: Inhibitory activity against Caspase 8	ic50	0.0500	uM
5-[[5-[[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl]thiophen-2-yl]methylsulfamoyl]-2-hydroxybenzoic acid	1795219: Fluorometric Assay from Article 10.1021/jm020230j: “Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.”	ki	0.0500	uM
N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-1-[(naphthalene-1-carbonylamino)carbamoyl]cyclohexane-1-carboxamide	269767: Inhibition of caspase8	ic50	0.0700	uM
(4S)-4-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-5-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	49720: Inhibitory concentration of compound required against Caspase-8 enzyme compared to acylated dipeptides	ic50	0.0800	uM
(4S)-4-[[(2R)-2-acetamido-2-carboxyacetyl]amino]-5-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	49718: Inhibitory concentration of compound required against Caspase-8 compared to acylated dipeptides	ic50	0.0800	uM
N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-1-[(naphthalene-1-carbonylamino)carbamoyl]cyclopentane-1-carboxamide	269767: Inhibition of caspase8	ic50	0.0900	uM
(3S)-5-benzylsulfanyl-3-[[(2S)-2-[[(2R)-2-(5-bromo-2-methoxyphenyl)pent-4-ynoyl]amino]-3-methylbutanoyl]amino]-4-oxopentanoic acid	1796465: Caspase Inhibition Assay from Article 10.1016/j.bmcl.2005.05.116: “Lipophilic versus hydrogen-bonding effect in P3 on potency and selectivity of valine aspartyl ketones as caspase 3 inhibitors.”	ic50	0.0920	uM
(3S)-5-benzylsulfanyl-3-[[(2S)-2-[[2-hydroxy-2-(5-iodo-2-methoxyphenyl)acetyl]amino]-3-methylbutanoyl]amino]-4-oxopentanoic acid	1796465: Caspase Inhibition Assay from Article 10.1016/j.bmcl.2005.05.116: “Lipophilic versus hydrogen-bonding effect in P3 on potency and selectivity of valine aspartyl ketones as caspase 3 inhibitors.”	ic50	0.0980	uM
(3S)-5-benzylsulfanyl-3-[[(2S)-2-[[(2R)-2-hydroxy-2-(5-iodo-2-methoxyphenyl)acetyl]amino]-3-methylbutanoyl]amino]-4-oxopentanoic acid	240544: Inhibitory activity against recombinant human Caspase-8	ic50	0.0980	uM
(3S)-3-[[(2S)-2-[[(2S)-3-methyl-2-(3-phenylpropanoylamino)butanoyl]amino]propanoyl]amino]-4-oxo-7-phenylheptanoic acid	2100634: Binding affinity to Caspase-8 (unknown origin) using Ac-IETD-AFC as substrate assessed as inhibition constant	ki	0.1000	uM
(3S)-5-benzylsulfanyl-3-[[(2S)-2-[[2-(5-bromo-2-methoxyphenyl)-2-hydroxyacetyl]amino]-3-methylbutanoyl]amino]-4-oxopentanoic acid	1796465: Caspase Inhibition Assay from Article 10.1016/j.bmcl.2005.05.116: “Lipophilic versus hydrogen-bonding effect in P3 on potency and selectivity of valine aspartyl ketones as caspase 3 inhibitors.”	ic50	0.1040	uM
(3S)-5-benzylsulfanyl-3-[[(2S)-2-[[(2R)-2-(5-bromo-2-methoxyphenyl)-2-hydroxyacetyl]amino]-3-methylbutanoyl]amino]-4-oxopentanoic acid	240544: Inhibitory activity against recombinant human Caspase-8	ic50	0.1040	uM
(4S,7S,11aS)-7-benzamido-2-(benzenesulfonyl)-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-6-oxo-3,4,7,8,9,10,11,11a-octahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	257629: Inhibitory activity against Caspase 8	ic50	0.1060	uM
N-[(6S)-3-(benzenesulfonamidomethyl)-1-[2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-2-oxoethyl]-7-oxo-5,6-dihydro-2H-azepin-6-yl]naphthalene-2-carboxamide	293086: Inhibition of caspase 8	ic50	0.1090	uM
N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-1-[(naphthalene-1-carbonylamino)carbamoyl]cyclobutane-1-carboxamide	269767: Inhibition of caspase8	ic50	0.1300	uM
(4S)-4-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-5-[[(2S)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	1796494: Caspase Inhibition Assay from Article 10.1016/j.bmcl.2003.10.064: “Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors.”	ic50	0.1300	uM
5-[[4-[[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl]phenyl]methylsulfamoyl]-2-hydroxybenzoic acid	1795219: Fluorometric Assay from Article 10.1021/jm020230j: “Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.”	ki	0.1500	uM
(4S,7S,11aS)-2-(benzenesulfonyl)-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-7-(isoquinoline-1-carbonylamino)-6-oxo-3,4,7,8,9,10,11,11a-octahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	257629: Inhibitory activity against Caspase 8	ic50	0.1600	uM
N-[(6S)-1-[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-1-oxopropan-2-yl]-7-oxo-5,6-dihydro-2H-azepin-6-yl]naphthalene-2-carboxamide	293086: Inhibition of caspase 8	ic50	0.1620	uM
(3S)-3-[2-[5-tert-butyl-2-oxo-3-(2H-tetrazol-5-ylamino)pyrazin-1-yl]butanoylamino]-5-[hexyl(methyl)amino]-4-oxopentanoic acid;2,2,2-trifluoroacetic acid	306146: Inhibition of human recombinant caspase 8	ic50	0.1635	uM
(3S)-3-[[(2S)-4-methyl-2-[[2-(naphthalen-1-ylamino)-2-oxoacetyl]amino]pentanoyl]amino]-4-oxobutanoic acid	49706: Binding affinity towards human Caspase-8	ic50	0.1790	uM
3-[2-[[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-2-oxoethoxy]naphthalene-2-carboxylic acid	49719: Inhibition of Caspase-8 enzyme	ic50	0.2000	uM
(3S)-3-[[(2S)-2-[3-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-2-oxo-1-pyridinyl]butanoyl]amino]-5-benzylsulfanyl-4-oxopentanoic acid	241559: Inhibitory concentration against recombinant human caspase-8 in neuronal precursor (NT2) cells	ic50	0.2200	uM
1-[[(2,6-dimethylbenzoyl)amino]carbamoyl]-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]cyclohexane-1-carboxamide	269767: Inhibition of caspase8	ic50	0.2300	uM
(4S,7S,11aS)-7-benzamido-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-2-methyl-6-oxo-3,4,7,8,9,10,11,11a-octahydro-1H-pyrazino[1,2-a]azocine-4-carboxamide	257629: Inhibitory activity against Caspase 8	ic50	0.2470	uM
(4S,7S,11aS)-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-7-(isoquinoline-1-carbonylamino)-6-oxo-3,4,7,8,9,10,11,11a-octahydro-1H-[1,4]oxazino[4,3-a]azocine-4-carboxamide	257629: Inhibitory activity against Caspase 8	ic50	0.2640	uM

CTD chemical–gene interactions

732 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	affects activity, increases expression, increases cleavage, increases reaction, affects cotreatment (+4 more)	33
Bortezomib	increases reaction, affects cleavage, affects reaction, increases phosphorylation, affects cotreatment (+6 more)	32
Doxorubicin	increases activity, affects expression, decreases expression, decreases reaction, affects response to substance (+8 more)	29
Cisplatin	decreases reaction, increases activity, affects cotreatment, increases expression, increases cleavage (+7 more)	28
benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone	increases activity, decreases activity, increases localization, decreases expression, affects reaction (+6 more)	26
Resveratrol	affects response to substance, increases activity, increases reaction, affects localization, increases expression (+8 more)	21
Acetylcysteine	increases activity, decreases reaction, increases expression, affects cotreatment, increases cleavage (+4 more)	19
Fluorouracil	decreases reaction, increases cleavage, affects expression, increases activity, affects cotreatment (+5 more)	19
Quercetin	increases reaction, increases cleavage, affects localization, decreases expression, increases expression (+3 more)	18
Vorinostat	affects localization, increases activity, affects response to substance, affects binding, affects cotreatment (+4 more)	16
Plant Extracts	affects expression, increases expression, increases activity, increases cleavage, decreases activity (+3 more)	14
Paclitaxel	increases cleavage, increases expression, increases reaction, decreases expression, affects cotreatment (+1 more)	13
Valproic Acid	increases expression, increases cleavage, increases reaction, affects expression, increases activity (+3 more)	11
sodium arsenite	increases expression, increases abundance, increases response to substance, decreases methylation, decreases reaction (+6 more)	10
Decitabine	affects expression, increases activity, increases expression, decreases expression, increases cleavage (+7 more)	10
Cadmium Chloride	increases expression, increases methylation, affects reaction, affects expression, increases activity (+5 more)	10
bisphenol A	increases reaction, increases cleavage, increases activity, increases expression, decreases expression (+1 more)	9
pyrazolanthrone	affects cotreatment, increases cleavage, increases reaction, decreases reaction, increases expression (+1 more)	9
Curcumin	increases cleavage, increases reaction, affects cotreatment, increases expression, decreases reaction (+2 more)	8
trichostatin A	increases activity, increases cleavage, affects expression, affects methylation, increases expression (+1 more)	7
benzyloxycarbonyl-valyl-alanyl-aspartic acid	increases cleavage, affects localization, decreases expression, decreases reaction, increases activity (+1 more)	7
Sorafenib	decreases reaction, increases cleavage, increases activity, affects binding, increases reaction (+2 more)	7
Gemcitabine	affects activity, increases activity, increases cleavage, decreases reaction, affects reaction (+2 more)	7
Aspirin	increases cleavage, increases expression, affects reaction, increases localization, affects cotreatment (+1 more)	7
Camptothecin	affects cleavage, increases cleavage, increases expression, affects reaction, decreases reaction (+3 more)	7
Mitomycin	increases activity, increases cleavage	7
fludarabine	affects cotreatment, increases cleavage, decreases reaction, increases activity	6
alvocidib	affects cotreatment, increases cleavage, increases activity	6
SB 203580	affects cotreatment, increases activity, decreases reaction, increases cleavage, increases reaction	6
Celecoxib	increases cleavage, increases reaction, affects cotreatment, increases activity, decreases reaction	6

ChEMBL screening assays

116 unique, capped per target: 106 binding, 10 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1020510	Binding	Inhibition of caspase 8 assessed as ratio of rate constant k3 to Ki for enzyme	Synthesis and structure-activity relationships of oxamyl dipeptide caspase inhibitors developed for the treatment of liver disease. — *Bioorg Med Chem Lett*
CHEMBL5723093	Functional	Affinity Biochemical interaction: (enzymatic assay (fluorogenic substrate cleavage)) EUB0002173aAD CASP8	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

15 cell lines: 15 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1M6	Abcam HeLa CASP8 KO	Cancer cell line	Female
CVCL_B8CG	Abcam HCT 116 CASP8 KO	Cancer cell line	Male
CVCL_B8TB	Abcam MCF-7 CASP8 KO	Cancer cell line	Female
CVCL_B9EM	Abcam A-549 CASP8 KO	Cancer cell line	Male
CVCL_D6AJ	HyCyte A-549 KO-hCASP8	Cancer cell line	Male
CVCL_D9ZG	Ubigene HeLa CASP8 KO	Cancer cell line	Female
CVCL_F5AE	EDITGENE CASP8 Knockout A549 Cell Line	Cancer cell line	Male
CVCL_F5BU	EDITGENE caspase 8 Knockout L-02 Cell Line	Cancer cell line	Female
CVCL_JL62	VU-SCC-040	Cancer cell line	Female
CVCL_SG98	HAP1 CASP8 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00158041	Phase 4	COMPLETED	Subcutaneous Amifostine Safety Study
NCT00277160	Phase 4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00365508	Phase 4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00440960	Phase 4	COMPLETED	Anesthesia in Flexible Bronchoscopy for Lung Cancer Diagnostic
NCT00492843	Phase 4	TERMINATED	Loading Dose or Standard Dose of Intravenous Ibandronate in Treating Patients With Lung Cancer and Skeletal Metastasis
NCT00666978	Phase 4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00675168	Phase 4	UNKNOWN	Positron Emission Tomography (PET)/Computed Tomography (CT) and Roentgen in Lung Cancer: Evaluation of Patients in General Practice
NCT00712647	Phase 4	COMPLETED	Carotene and Retinol Efficacy Trial
NCT00747773	Phase 4	COMPLETED	Cryospray Ablation of Surgical Resection Specimens To Determine Safety And Histological Effect In The Lung
NCT01060137	Phase 4	COMPLETED	Fentanyl Matrix in Lung Cancer Pain
NCT01381627	Phase 4	UNKNOWN	Safety Evaluation of Dexmedetomidine for EBUS-TBNA
NCT01741506	Phase 4	COMPLETED	Coagulation Profile in Patients Undergoing Video Assisted Thorascopic Surgery (VATS) for Lung Cancer
NCT02246023	Phase 4	COMPLETED	Fractionated Versus Target-controlled Propofol Administration in Bronchoscopy
NCT02275702	Phase 4	COMPLETED	Randomized Study of Preoperative Dexamethasone for Quality of Recovery in VATS Lung Resection Patients
NCT02346318	Phase 4	UNKNOWN	The Randomized Controlled Clinical Trial of Kushen Injection
NCT02476526	Phase 4	COMPLETED	Safety of Low Dose IV Contrast CT Scanning in Chronic Kidney Disease
NCT02490059	Phase 4	COMPLETED	Ultrathin Bronchoscopy for Solitary Pulmonary Nodules
NCT02504801	Phase 4	UNKNOWN	Efficacy of Nebulized Pulmicort Respules in Primary Lung Cancer Patients With COPD
NCT02869789	Phase 4	COMPLETED	An Investigational Immuno-therapy Study for Safety of Nivolumab in Combination With Ipilimumab to Treat Advanced Cancers
NCT03302221	Phase 4	WITHDRAWN	Regional Haemodynamic Changes in Radial Artery Assessment With Continuous Pulsed-wave Doppler Ultrasound
NCT03313544	Phase 4	UNKNOWN	Evolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03394222	Phase 4	COMPLETED	Effect of Preoperative Budesonide Inhalation on Arterial Blood Oxygenation and Intrapulmonary Shunt During OLV
NCT03570645	Phase 4	COMPLETED	Comparison of the Duration of Ropivacaine Combined With Dexmedetomidine or Dexamethasone on Paravertebral Block
NCT03571126	Phase 4	UNKNOWN	Olanzapine for the Prevention and Treatment of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer
NCT03642457	Phase 4	TERMINATED	Efficacy Between Serratus Plane Block And Local Infiltration In Vats
NCT04145570	Phase 4	COMPLETED	A Single-Dose,ComparativeBioavailability Study ofTwo Formulations ofErlotinib150mgTabletsunderFastingConditions
NCT04155008	Phase 4	TERMINATED	Nutrition and Pharmacological Algorithm for Oncology Patients Study
NCT04613284	Phase 4	UNKNOWN	Rh-Endostatin Combined With CCRT(50 Gy) Followed by Durvalumab Maintenance for the Treatment of Specific Phase III NSCLC
NCT05463913	Phase 4	RECRUITING	Lung Nodule Detection Using Ultra-long FOV PET/CT
NCT05521789	Phase 4	RECRUITING	Erector Spinae Block for Thoracic Surgery
NCT05525338	Phase 4	RECRUITING	Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels
NCT05663242	Phase 4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Lung Tumors and Its Mechanism of Action
NCT05926336	Phase 4	UNKNOWN	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06105801	Phase 4	RECRUITING	EBUS-TBNA vs Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing
NCT06276933	Phase 4	NOT_YET_RECRUITING	A Study of Camrelizumab Combined With Chemotherapy ± Thalidomide in First-line Treatment of Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
NCT06646471	Phase 4	RECRUITING	PROspective Master-protocol for Evaluation of Systemic THErapeutics in Elderly With Thoracic Malignancies
NCT07405086	Phase 4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT07743333	Phase 4	COMPLETED	Nebulized Lidocaine And Ketamine Before Fiberoptic Bronchoscopy
NCT07761351	Phase 4	RECRUITING	A Randomized Controlled Trial Comparing Percutaneous CT-Guided Biopsy and Shape-Sensing Robotic-Assisted Bronchoscopy
NCT07802847	Phase 4	NOT_YET_RECRUITING	Innovative and Cooperative Pathway Integrating Oncogeriatric, Pharmaceutical and Pharmacological Follow-up in Elderly Patients.
NCT00002550	Phase 3	COMPLETED	Chemotherapy Plus Radiation Therapy With or Without Surgery in Treating Patients With Stage IIIA Non-small Cell Lung Cancer
NCT00002583	Phase 3	COMPLETED	Vinorelbine + Cisplatin or No Further Therapy in Non-small Cell Lung Cancer That Has Been Surgically Removed
NCT00002623	Phase 3	COMPLETED	Chemotherapy Followed by Surgery or Radiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer
NCT00002822	Phase 3	COMPLETED	Combination Chemotherapy Followed by Radiation Therapy in Patients With Small Cell Lung Cancer
NCT00002823	Phase 3	COMPLETED	Combination Chemotherapy Compared With No Treatment Following Surgery in Treating Patients With Non-small Cell Lung Cancer
NCT00002858	Phase 3	UNKNOWN	Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Small Cell Lung Cancer
NCT00002911	Phase 3	COMPLETED	Marimastat in Treating Patients With Stage III Non-small Cell Lung Cancer
NCT00003011	Phase 3	COMPLETED	Marimastat Following Chemotherapy in Treating Patients With Small Cell Lung Cancer
NCT00003053	Phase 3	UNKNOWN	Combination Chemotherapy in Treating Patients With Stage I, II, or IIIA Non-small Cell Lung Cancer That Has Been Surgically Removed
NCT00003117	Phase 3	COMPLETED	Paclitaxel With or Without Carboplatin in Treating Patients With Advanced Non-small Cell Lung Cancer
NCT00003159	Phase 3	COMPLETED	Surgery With or Without Preoperative Chemotherapy in Treating Patients With Resectable Non-small Cell Lung Cancer
NCT00003235	Phase 3	COMPLETED	Combination Chemotherapy Plus Radiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer That Can Not Be Surgically Removed
NCT00003240	Phase 3	UNKNOWN	Standard Therapy Given With or Without Combination Chemotherapy in Treating Patients With Non-small Cell Lung Cancer
NCT00003279	Phase 3	COMPLETED	Vaccination Therapy in Treating Patients With Limited-Stage Small Cell Lung Cancer
NCT00003299	Phase 3	COMPLETED	Cisplatin Plus Etoposide With or Without Paclitaxel in Treating Patients With Extensive-Stage Small Cell Lung Cancer
NCT00003313	Phase 3	COMPLETED	Amifostine in Treating Patients With Stage II or Stage III Non-small Cell Lung Cancer
NCT00003317	Phase 3	COMPLETED	Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Stage IIIA Non-small Cell Lung Cancer
NCT00003364	Phase 3	COMPLETED	Radiation Therapy Plus Combination Chemotherapy In Treating Patients With Limited Stage Small Cell Lung Cancer
NCT00003387	Phase 3	COMPLETED	Carboplatin, Paclitaxel, and Radiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer That Cannot Be Removed During Surgery
NCT00003447	Phase 3	UNKNOWN	Vinorelbine and/or Gemcitabine in Treating Older Patients With Stage IIIB or Stage IV Non-small Cell Lung Cancer

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CASP8 across ~30M SureChEMBL compounds — explore on Sugi Predict.