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
• Clinical variants (ClinVar): 406 total — 19 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes — 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
• MANE Select transcript: NM_001372051

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: 26 — 18 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000264275, ENST00000323492, ENST00000339403, ENST00000358485, ENST00000392258, ENST00000392263, ENST00000413726, ENST00000429881, ENST00000432109, ENST00000437283, ENST00000440732, ENST00000444430, ENST00000447616, ENST00000450491, ENST00000471383, ENST00000490412, ENST00000490682, ENST00000673742, ENST00000696066, ENST00000696067, ENST00000696068, ENST00000696069, ENST00000696085, ENST00000696086, ENST00000696087, ENST00000957923

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.

FANTOM5 promoters (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

288 total, 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

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

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)

56 targeting CASP8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

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

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)

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 (11): Q14790, A0A8Q3SI66, A0A8Q3SID9, A0A8Q3WKY8, C9JB29, E7EQ01, E7EQ06, E7ETB7, E7EVN1, 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 23, strand 21, 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)

36 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4JJ7	X-RAY DIFFRACTION	1.18
1QTN	X-RAY DIFFRACTION	1.2
7LVM	X-RAY DIFFRACTION	1.47
6X8H	X-RAY DIFFRACTION	1.48
7LVJ	X-RAY DIFFRACTION	1.5
4PS1	X-RAY DIFFRACTION	1.73
2Y1L	X-RAY DIFFRACTION	1.8
3KJN	X-RAY DIFFRACTION	1.8
3KJQ	X-RAY DIFFRACTION	1.8
3H11	X-RAY DIFFRACTION	1.9
2C2Z	X-RAY DIFFRACTION	1.95
8YM5	X-RAY DIFFRACTION	2.09
6AGW	X-RAY DIFFRACTION	2.09
4PRZ	X-RAY DIFFRACTION	2.12
4ZBW	X-RAY DIFFRACTION	2.2
8YM4	X-RAY DIFFRACTION	2.34
1QDU	X-RAY DIFFRACTION	2.8
6PX9	X-RAY DIFFRACTION	2.88
1F9E	X-RAY DIFFRACTION	2.9
1I4E	X-RAY DIFFRACTION	3
2FUN	X-RAY DIFFRACTION	3
8YD8	X-RAY DIFFRACTION	3.11
5JQE	X-RAY DIFFRACTION	3.16
5H31	X-RAY DIFFRACTION	3.17
8YM6	X-RAY DIFFRACTION	3.3
8YD7	X-RAY DIFFRACTION	3.32
8YNM	ELECTRON MICROSCOPY	3.49
8YNL	ELECTRON MICROSCOPY	3.55
5H33	X-RAY DIFFRACTION	3.6
8YNK	ELECTRON MICROSCOPY	3.62

Predicted structure (AlphaFold)

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

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): 384–385 (cleavage; by autocatalytic cleavage); 317; 360; 216–217 (cleavage; by autocatalytic cleavage); 374–375 (cleavage; by casp6)

Post-translational modifications (7): 188, 211, 224, 334, 380, 387, 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 mig
387	impaired cdk1-mediated phosphorylation and enhanced apoptosis.
413	abolished adp-riboxanation by c.violaceum copc.

Function

Pathways and Gene Ontology

Reactome pathways

59 pathways

ID	Pathway
R-HSA-111465	Apoptotic cleavage of cellular proteins
R-HSA-140534	Caspase activation via Death Receptors in the presence of ligand
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-2562578	TRIF-mediated programmed cell death
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins
R-HSA-3371378	Regulation by c-FLIP
R-HSA-5213460	RIPK1-mediated regulated necrosis
R-HSA-5218900	CASP8 activity is inhibited
R-HSA-5357786	TNFR1-induced proapoptotic signaling
R-HSA-5357905	Regulation of TNFR1 signaling
R-HSA-5660668	CLEC7A/inflammasome pathway
R-HSA-5675482	Regulation of necroptotic cell death
R-HSA-69416	Dimerization of procaspase-8
R-HSA-75108	Activation, myristolyation of BID and translocation to mitochondria
R-HSA-75153	Apoptotic execution phase
R-HSA-75157	FasL/ CD95L signaling
R-HSA-75158	TRAIL signaling
R-HSA-9013957	TLR3-mediated TICAM1-dependent programmed cell death
R-HSA-933543	NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10
R-HSA-9686347	Microbial modulation of RIPK1-mediated regulated necrosis
R-HSA-9693928	Defective RIPK1-mediated regulated necrosis
R-HSA-9758274	Regulation of NF-kappa B signaling
R-HSA-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade

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 (48): 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), obsolete proteolysis involved in protein catabolic process (GO:0051603), 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), autophagosome assembly (GO:0000045)

GO Molecular Function (12): 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), protein binding (GO:0005515), 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), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-17 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
lymphocyte activation	3
response to lipid	2
response to oxygen-containing compound	2
tumor necrosis factor receptor superfamily binding	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

Protein interactions and networks

STRING

4258 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP8	FADD	Q13158	999
CASP8	RIPK3	Q9Y572	998
CASP8	RIPK1	Q13546	998
CASP8	FAS	P25445	998
CASP8	TNFRSF1A	P19438	997
CASP8	TRADD	Q15628	997
CASP8	CFLAR	O15519	992
CASP8	FASLG	P48023	992
CASP8	TNFRSF10B	O14763	991
CASP8	CASP1	P29466	986
CASP8	CASP10	Q92851	985
CASP8	CASP3	P42574	984
CASP8	BCL10	O95999	984
CASP8	CARD9	Q9H257	975
CASP8	MALT1	Q9UDY8	974

IntAct

290 interactions, top by confidence:

A	B	Type	Score
CASP8	FADD	psi-mi:“MI:0914”(association)	0.980
CASP8	FADD	psi-mi:“MI:0915”(physical association)	0.980
FADD	CASP8	psi-mi:“MI:0915”(physical association)	0.980
CASP8	FADD	psi-mi:“MI:0407”(direct interaction)	0.980
FADD	CASP8	psi-mi:“MI:0914”(association)	0.980
CASP8	RIPK1	psi-mi:“MI:0914”(association)	0.960
RIPK1	CASP8	psi-mi:“MI:0915”(physical association)	0.960

BioGRID (492): CASP8 (Reconstituted Complex), CASP8 (Reconstituted Complex), CASP8 (Affinity Capture-Western), PRDX6 (Affinity Capture-Western), CASP8 (PCA), ced-4 (Affinity Capture-Western), CFLAR (Biochemical Activity), CASP8 (Co-fractionation), CASP8 (Affinity Capture-MS), RIPK1 (Affinity Capture-Western), FADD (Affinity Capture-Western), CFLAR (Affinity Capture-Western), CASP10 (Affinity Capture-Western), TICAM1 (Affinity Capture-Western), CASP8 (Affinity Capture-Western)

ESM2 similar proteins: A0A1D5PPP7, F1NV61, O01382, O02002, O08738, O35397, O89094, O89110, P29452, P29594, P31944, P42574, P42575, P43527, P55211, P55212, P55213, P55215, P55865, P55866, P55867, P70343, P70677, P89116, Q08DY9, Q0IIM3, Q14344, Q14790, Q153Z0, Q2PFV2, Q3T0P5, Q504J1, Q5IS54, Q5IS99, Q60431, Q60446, Q61699, Q66HA8, Q8BLR2, Q8C3Q9

Diamond homologs: A0A1D5PPP7, F1NV61, O01382, O02002, O08738, O35397, O89110, P29452, P42573, P42574, P55210, P55211, P55212, P55213, P55214, P55866, P70677, P89116, P97864, Q08DY9, Q14790, Q2PFV2, Q3T0P5, Q5IS54, Q5IS99, Q60431, Q8C3Q9, Q8MJC3, Q8MJU1, Q8MKI5, Q92851, Q95ND5, Q9JHX4, G5EBM1, G5ECW5, O15519, O89094, P31944, P42575, P45436

SIGNOR signaling

47 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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 67 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	8	114.9×	9e-14
RIPK1-mediated regulated necrosis	10	86.2×	9e-16
TNFR1-induced NF-kappa-B signaling pathway	8	50.7×	2e-10
TNFR1-induced proapoptotic signaling	6	49.7×	1e-07
Regulation of TNFR1 signaling	10	42.2×	2e-12
Regulation of necroptotic cell death	5	41.4×	5e-06
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	5	33.7×	1e-05
NOD1/2 Signaling Pathway	5	29.9×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
extrinsic apoptotic signaling pathway via death domain receptors	10	73.0×	4e-14
positive regulation of extrinsic apoptotic signaling pathway	7	58.0×	5e-09
tumor necrosis factor-mediated signaling pathway	7	42.0×	3e-08
extrinsic apoptotic signaling pathway	7	39.0×	5e-08
positive regulation of neuron apoptotic process	7	34.6×	1e-07
canonical NF-kappaB signal transduction	5	33.3×	2e-05
obsolete positive regulation of NF-kappaB transcription factor activity	8	29.9×	3e-08
apoptotic signaling pathway	6	24.5×	1e-05

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.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	6
Uncertain significance	183
Likely benign	132
Benign	27

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1394714	NM_001372051.1(CASP8):c.879T>A (p.Tyr293Ter)	Pathogenic
1935186	NM_001372051.1(CASP8):c.306-1930dup	Pathogenic
2037856	NM_001372051.1(CASP8):c.679C>T (p.Gln227Ter)	Pathogenic
2072614	NM_001372051.1(CASP8):c.306-1954_306-1953del	Pathogenic
2130976	NM_001372051.1(CASP8):c.429_430insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNGGAAGCTCCCAAGATGACTACCTCCAGCCTCTGGCCACAGGGAACCTTCTTCATATCCCACAAGCAAAGGAGCTGGATATTTTC (p.Phe143_Ile144insPhePhePhePhePhePheXaaXaaXaaXaaGlySerSerGlnAspAspTyrLeuGlnProLeuAlaThrGlyAsnLeuLeuHisIleProGlnAlaLysGluLeuAspIlePhe)	Pathogenic
2186059	NM_001372051.1(CASP8):c.983dup (p.Gln329fs)	Pathogenic
2762094	NM_001372051.1(CASP8):c.492_493del (p.Ala165fs)	Pathogenic
2790366	NM_001372051.1(CASP8):c.306-1976del	Pathogenic
2885998	NM_001372051.1(CASP8):c.306-1978G>T	Pathogenic
2896117	NM_001372051.1(CASP8):c.918del (p.Asn306fs)	Pathogenic
3247245	NC_000002.11:g.(?202131210)(202151317_?)del	Pathogenic
3247246	NC_000002.11:g.(?202131210)(202134348_?)del	Pathogenic
4812021	NM_001372051.1(CASP8):c.613dup (p.Val205fs)	Pathogenic
4847516	NM_001372051.1(CASP8):c.691A>T (p.Lys231Ter)	Pathogenic
631840	NM_001372051.1(CASP8):c.1165C>T (p.Gln389Ter)	Pathogenic
7761	NM_001372051.1(CASP8):c.1228_1229del (p.Val410fs)	Pathogenic
946113	NM_001372051.1(CASP8):c.202C>T (p.Arg68Ter)	Pathogenic
968654	NM_001372051.1(CASP8):c.306-1949_306-1947delinsC	Pathogenic
973624	NM_001372051.1(CASP8):c.1303C>T (p.Arg435Ter)	Pathogenic
1068184	NM_001372051.1(CASP8):c.306-1910G>A	Likely pathogenic
1516540	NM_001372051.1(CASP8):c.411+1G>C	Likely pathogenic
3065576	NM_001372051.1(CASP8):c.320del (p.Gln107fs)	Likely pathogenic
3652746	NM_001372051.1(CASP8):c.306-1G>A	Likely pathogenic
4707109	NM_001372051.1(CASP8):c.306-2007G>T	Likely pathogenic
830621	NC_000002.12:g.(?201276807)(201276988_?)dup	Likely pathogenic

SpliceAI

4217 predictions. Top by Δscore:

Variant	Effect	Δscore
2:201266653:A:T	donor_gain	1.0000
2:201271514:AG:A	acceptor_gain	1.0000
2:201271515:GG:G	acceptor_gain	1.0000
2:201272633:CTTAG:C	acceptor_loss	1.0000
2:201272636:A:AG	acceptor_gain	1.0000
2:201272636:AG:A	acceptor_loss	1.0000
2:201272637:G:GG	acceptor_gain	1.0000
2:201284811:TTCA:T	acceptor_loss	1.0000
2:201284812:TCA:T	acceptor_loss	1.0000
2:201284813:CA:C	acceptor_loss	1.0000
2:201284814:A:AG	acceptor_gain	1.0000
2:201284814:AG:A	acceptor_gain	1.0000
2:201284814:AGG:A	acceptor_gain	1.0000
2:201284814:AGGG:A	acceptor_gain	1.0000
2:201284815:G:GC	acceptor_loss	1.0000
2:201284815:G:GG	acceptor_gain	1.0000
2:201284815:GG:G	acceptor_gain	1.0000
2:201284815:GGG:G	acceptor_gain	1.0000
2:201284815:GGGG:G	acceptor_gain	1.0000
2:201288782:C:CC	acceptor_gain	1.0000
2:201289428:A:AC	donor_gain	1.0000
2:201289429:G:C	donor_gain	1.0000
2:201289455:A:AC	donor_gain	1.0000
2:201289456:C:CC	donor_gain	1.0000
2:201289458:T:TA	donor_gain	1.0000
2:201289475:T:TA	donor_gain	1.0000
2:201289691:CTCA:C	donor_loss	1.0000
2:201289692:TCAC:T	donor_loss	1.0000
2:201289693:CA:C	donor_loss	1.0000
2:201289695:CCT:C	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000016651 (2:201252419 G>A,T), RS1000025369 (2:201234223 C>A,T), RS1000153701 (2:201281297 G>C), RS1000177894 (2:201236298 A>G), RS1000369807 (2:201247365 A>G), RS1000401871 (2:201239947 T>C), RS1000404895 (2:201253202 T>A,C), RS1000435895 (2:201233194 A>G), RS1000470087 (2:201232844 A>G), RS1000591594 (2:201275151 T>G), RS1000755005 (2:201245570 T>C), RS1000869259 (2:201259978 T>G), RS1000946326 (2:201272417 G>A), RS1000980747 (2:201286115 G>A), RS1000983471 (2:201260438 G>A)

Disease associations

OMIM: gene MIM:601763 | disease phenotypes: MIM:607271, MIM:211980, MIM:114550, MIM:114480

GenCC curated gene-disease

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

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autoimmune lymphoproliferative syndrome type 2B	Definitive	AR

Mondo (4): autoimmune lymphoproliferative syndrome type 2B (MONDO:0011804), lung cancer (MONDO:0008903), hepatocellular carcinoma (MONDO:0007256), hereditary breast carcinoma (MONDO:0016419)

Orphanet (3): Autoimmune lymphoproliferative syndrome-recurrent viral infections due to CASP8 deficiency (Orphanet:275517), Hereditary breast cancer (Orphanet:227535), Hepatocellular carcinoma (Orphanet:88673)

HPO phenotypes

28 total (28 of 28 shown, 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 total IgM
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 vaccine

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST001267_3	Melanoma	9.000000e-10
GCST002073_6	Chronic lymphocytic leukemia	3.000000e-09
GCST002318_138	Rheumatoid arthritis	3.000000e-09
GCST002318_177	Rheumatoid arthritis	2.000000e-09
GCST002568_7	Esophageal squamous cell carcinoma	4.000000e-13
GCST002842_11	Basal cell carcinoma	2.000000e-09
GCST003468_3	Chronic lymphocytic leukemia	3.000000e-08
GCST004113_1	Basal cell carcinoma	4.000000e-18
GCST004142_2	Melanoma	9.000000e-10
GCST004146_3	Chronic lymphocytic leukemia	5.000000e-11
GCST004627_88	Lymphocyte count	2.000000e-19
GCST004988_16	Breast cancer	2.000000e-16
GCST006085_115	Prostate cancer	2.000000e-08
GCST006959_113	Rheumatoid arthritis	5.000000e-07
GCST006959_72	Rheumatoid arthritis	3.000000e-07
GCST007505_29	Nevus count or cutaneous melanoma	4.000000e-06
GCST008834_5	Non-small cell lung cancer	4.000000e-08
GCST009597_203	Multiple sclerosis	1.000000e-06
GCST010303_41	Nevus count or cutaneous melanoma	3.000000e-12
GCST010304_76	Cutaneous malignant melanoma	2.000000e-12
GCST90002399_123	Neutrophil percentage of white cells	6.000000e-16
GCST90002400_340	Plateletcrit	8.000000e-27
GCST90002407_31	White blood cell count	4.000000e-15
GCST90013410_37	Basal cell carcinoma	7.000000e-47
GCST90016667_22	Spleen volume	3.000000e-09

EFO canonical traits (4, from GWAS)

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 (2)

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
C562840	Breast Cancer, Familial (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

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

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 3,430 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL43128	PRIMAQUINE PHOSPHATE	4	2,032
CHEMBL437526	PRALNACASAN	2	1,398

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items; also 1 prognostic.

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

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6736233	CASP8		0.00	0

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)

77 measured of 128 human assays (128 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(4S)-4-{[(1S)-1-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}-2-hydroxypropyl]carbamoyl}-4-[(2S)-2-acetamido-3-methylpentanamido]butanoic acid	IC50	4.2 nM
5-{[(4-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}phenyl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	160 nM
(4S)-4-{[(1S)-1-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}-2-methylpropyl]carbamoyl}-4-[(3S)-3-acetamido-3-formamidopropanoic acid]butanoic acid	IC50	190 nM
4-oxo-4-(piperidin-1-yl)-N-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)butanamide	IC50	231 nM
2-oxo-1-phenyl-2-[(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]ethyl acetate	IC50	233 nM
3-Chloro-N-(1,2,3,4-tetrahydro-1,3,4-trioxoisoquinolin-6-yl)-propanamide	IC50	530 nM
N-(2-Methoxy-phenyl)-N-(1,3,4-trioxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-succinamide	IC50	537 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[2-hydroxy-2-(5-iodo-2-methoxyphenyl)acetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	675 nM
N-(1,3,4-Trioxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-succinamic acid	IC50	859 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[(3,5-dibromophenyl)formamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	860 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[(2R)-2-(5-bromo-2-methoxyphenyl)pent-4-ynamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	1030 nM
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]pyridin-2-ylmethyl}sulfamoyl)-2-hydroxy-benzoic Acid	KI	1500 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[2-(5-bromo-2-methoxyphenyl)-2-hydroxyacetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	1540 nM
(3S)-5-{[(2-chloro-6-fluorophenyl)methyl]sulfanyl}-3-[(2S)-2-[1-(5-methanesulfonyl-2-methoxyphenyl)acetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	1600 nM
(3S)-3-[(2S)-2-[(2S)-2-[(3S)-3-formamido-3-(phenylformamido)propanoic acid]propanamido]-3-methylbutanamido]-4-oxo-7-phenylheptanoic acid	IC50	1650 nM
Compound 3	IC50	1800 nM
(3S)-5-[(cyclohexylmethyl)sulfanyl]-3-[(2S)-2-[1-(2,5-dimethoxyphenyl)acetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	1800 nM
Thiophene Scaffold 66a	KI	1900 nM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-2-phenylacetyl]amino]-3-methylbutanoyl]amino]-5-methylsulfonylpent-4-enoic acid	IC50	2000 nM	US-9045524: Selective caspase inhibitors and uses thereof
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-{2-hydroxy-2-[2-methoxy-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]acetamido}-3-methylbutanamido]-4-oxopentanoic acid	IC50	2460 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[(5-fluoro-1H-indol-2-yl)formamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	2600 nM
(3S)-3-[(2S)-2-[1-(2,5-dimethoxyphenyl)acetamido]-3-methylbutanamido]-5-[(2-methylpropyl)sulfanyl]-4-oxopentanoic acid	IC50	2600 nM
Heterocyclic deriv. 69b	KI	2700 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[(2S)-2-hydroxy-3-methylbutanamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	3020 nM
valine aspartyl ketone 29	IC50	3040 nM
Thiophene Scaffold 66b	KI	3200 nM
isatin Michael acceptor (IMA) analogue, 18a	IC50	3300 nM
(3S)-3-[(2S)-2-{1-[5-(carboxymethoxy)-2-ethoxyphenyl]acetamido}-3-methylbutanamido]-5-{[(2-chloro-6-fluorophenyl)methyl]sulfanyl}-4-oxopentanoic acid	IC50	3800 nM
2-[2-(2-Adamantan-1-yl-4-methyl-phenoxy)-acetylamino]-4-methyl-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	3870 nM
isatin Michael acceptor (IMA) analogue, 12a	IC50	3880 nM
Pyridine Scaffold 4	KI	3900 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[(2S)-2-hydroxy-2-phenylacetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	4060 nM
isatin Michael acceptor (IMA) analogue, 11a	IC50	4100 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[(2R)-2-hydroxy-2-phenylacetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	4160 nM
isatin Michael acceptor (IMA) analogue, 18b	IC50	4180 nM
(3S)-5-{[(2-chloro-6-fluorophenyl)methyl]sulfanyl}-3-[(2S)-2-(1-{2-ethoxy-5-[2-oxo-2-(propan-2-yloxy)ethoxy]phenyl}acetamido)-3-methylbutanamido]-4-oxopentanoic acid	IC50	4200 nM
2-(2,3-dihydro-1,4-benzodioxin-2-yl)-4-[3-(trifluoromethyl)phenyl]-1,3-thiazole	KI	4300 nM
isatin Michael acceptor (IMA) analogue, 13b	IC50	4300 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[2-(2,5-dimethoxyphenyl)-2-hydroxyacetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	4490 nM
isatin Michael acceptor (IMA) analogue, 13a	IC50	4580 nM
isatin Michael acceptor (IMA) analogue, 19a	IC50	4700 nM
isatin Michael acceptor (IMA) analogue, 19b	IC50	4700 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[2-(5-acetyl-2-methoxyphenyl)-2-hydroxyacetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	4850 nM
(3S)-5-{[(2-chloro-6-fluorophenyl)methyl]sulfanyl}-3-[(2S)-2-[1-(2,5-dimethoxyphenyl)acetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	5000 nM
isatin Michael acceptor (IMA) analogue, 12c	IC50	5350 nM
isatin Michael acceptor (IMA) analogue, 13c	IC50	5350 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-{1-[2-methoxy-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]acetamido}-3-methylbutanamido]-4-oxopentanoic acid	IC50	5450 nM
N-(1,2,3,4-Tetrahydro-1,3,4-trioxoisoquinolin-7-yl)-4-nitrobenzamide	IC50	5670 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[(2S)-2-(5-bromo-2-methoxyphenyl)-3-phenylpropanamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	5810 nM
(3S)-5-(benzylsulfanyl)-3-[(2S)-2-[1-(5-acetyl-2-methoxyphenyl)acetamido]-3-methylbutanamido]-4-oxopentanoic acid	IC50	5900 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	increases expression, affects reaction, affects cotreatment, increases cleavage, increases activity (+4 more)	33
Bortezomib	increases response to substance, affects reaction, increases phosphorylation, decreases reaction, decreases expression (+6 more)	32
Doxorubicin	affects binding, increases response to substance, affects reaction, increases activity, affects activity (+8 more)	29
Cisplatin	decreases reaction, affects cotreatment, increases cleavage, decreases response to substance, affects expression (+7 more)	28
benzyloxycarbonyl-isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone	increases expression, increases localization, decreases response to substance, decreases expression, affects reaction (+6 more)	26
Resveratrol	increases cleavage, decreases reaction, increases activity, decreases response to substance, affects response to substance (+8 more)	21
Acetylcysteine	affects cotreatment, increases activity, increases reaction, increases expression, decreases reaction (+4 more)	19
Fluorouracil	increases response to substance, decreases reaction, decreases expression, affects expression, increases activity (+5 more)	19
Quercetin	increases reaction, decreases expression, increases expression, decreases reaction, affects cotreatment (+3 more)	18
Vorinostat	affects cotreatment, increases cleavage, affects localization, increases activity, affects response to substance (+4 more)	16
Plant Extracts	decreases activity, decreases response to substance, affects expression, decreases reaction, increases cleavage (+3 more)	14
Paclitaxel	increases activity, increases cleavage, increases expression, increases reaction, decreases expression (+1 more)	13
Valproic Acid	affects cotreatment, increases response to substance, increases expression, increases reaction, affects reaction (+3 more)	11
sodium arsenite	decreases reaction, increases cleavage, increases reaction, increases response to substance, decreases expression (+6 more)	10
Decitabine	increases cleavage, increases response to substance, affects methylation, decreases expression, decreases reaction (+7 more)	10
Cadmium Chloride	decreases expression, affects cotreatment, affects expression, increases abundance, increases activity (+5 more)	10
bisphenol A	increases activity, increases expression, decreases expression, decreases reaction, increases reaction (+1 more)	9
pyrazolanthrone	decreases reaction, increases expression, increases activity, affects cotreatment, increases cleavage (+1 more)	9
Curcumin	affects cotreatment, increases expression, decreases reaction, decreases expression, increases activity (+2 more)	8
trichostatin A	increases cleavage, affects expression, affects methylation, increases expression, affects cotreatment (+1 more)	7
benzyloxycarbonyl-valyl-alanyl-aspartic acid	decreases expression, decreases reaction, increases activity, affects cotreatment, increases cleavage (+1 more)	7
Sorafenib	affects binding, increases reaction, affects localization, affects cotreatment, decreases reaction (+2 more)	7
Gemcitabine	affects cotreatment, increases expression, affects activity, increases activity, increases cleavage (+2 more)	7
Aspirin	affects cotreatment, increases activity, increases cleavage, increases expression, affects reaction (+1 more)	7
Camptothecin	decreases expression, affects reaction, decreases reaction, increases activity, affects cleavage (+3 more)	7
Mitomycin	increases activity, increases cleavage	7
fludarabine	affects cotreatment, increases cleavage, decreases reaction, increases activity	6
alvocidib	increases cleavage, increases activity, affects cotreatment	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

13 cell lines: 13 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_JL62	VU-SCC-040	Cancer cell line	Female
CVCL_SG98	HAP1 CASP8 (-) 1	Cancer cell line	Male
CVCL_SG99	HAP1 CASP8 (-) 2	Cancer cell line	Male
CVCL_WV08	SJG-6	Cancer cell line	Female

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00158041	PHASE4	COMPLETED	Subcutaneous Amifostine Safety Study
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00365508	PHASE4	COMPLETED	Counseling and Nicotine Replacement Therapy in Helping Adult Smokers Quit Smoking
NCT00440960	PHASE4	COMPLETED	Anesthesia in Flexible Bronchoscopy for Lung Cancer Diagnostic
NCT00492843	PHASE4	TERMINATED	Loading Dose or Standard Dose of Intravenous Ibandronate in Treating Patients With Lung Cancer and Skeletal Metastasis
NCT00666978	PHASE4	COMPLETED	Health Education Counseling With or Without Bupropion in Helping African Americans Stop Smoking
NCT00675168	PHASE4	UNKNOWN	Positron Emission Tomography (PET)/Computed Tomography (CT) and Roentgen in Lung Cancer: Evaluation of Patients in General Practice
NCT00712647	PHASE4	COMPLETED	Carotene and Retinol Efficacy Trial
NCT00747773	PHASE4	COMPLETED	Cryospray Ablation of Surgical Resection Specimens To Determine Safety And Histological Effect In The Lung
NCT01060137	PHASE4	COMPLETED	Fentanyl Matrix in Lung Cancer Pain
NCT01381627	PHASE4	UNKNOWN	Safety Evaluation of Dexmedetomidine for EBUS-TBNA
NCT01741506	PHASE4	COMPLETED	Coagulation Profile in Patients Undergoing Video Assisted Thorascopic Surgery (VATS) for Lung Cancer
NCT02246023	PHASE4	COMPLETED	Fractionated Versus Target-controlled Propofol Administration in Bronchoscopy
NCT02275702	PHASE4	COMPLETED	Randomized Study of Preoperative Dexamethasone for Quality of Recovery in VATS Lung Resection Patients
NCT02346318	PHASE4	UNKNOWN	The Randomized Controlled Clinical Trial of Kushen Injection
NCT02476526	PHASE4	COMPLETED	Safety of Low Dose IV Contrast CT Scanning in Chronic Kidney Disease
NCT02490059	PHASE4	COMPLETED	Ultrathin Bronchoscopy for Solitary Pulmonary Nodules
NCT02504801	PHASE4	UNKNOWN	Efficacy of Nebulized Pulmicort Respules in Primary Lung Cancer Patients With COPD
NCT02869789	PHASE4	COMPLETED	An Investigational Immuno-therapy Study for Safety of Nivolumab in Combination With Ipilimumab to Treat Advanced Cancers
NCT03302221	PHASE4	WITHDRAWN	Regional Haemodynamic Changes in Radial Artery Assessment With Continuous Pulsed-wave Doppler Ultrasound
NCT03313544	PHASE4	UNKNOWN	Evolution of the Heart Function When Monitoring Immunotherapies Anti-cancerous Inhibiting PD-1
NCT03394222	PHASE4	COMPLETED	Effect of Preoperative Budesonide Inhalation on Arterial Blood Oxygenation and Intrapulmonary Shunt During OLV
NCT03570645	PHASE4	COMPLETED	Comparison of the Duration of Ropivacaine Combined With Dexmedetomidine or Dexamethasone on Paravertebral Block
NCT03571126	PHASE4	UNKNOWN	Olanzapine for the Prevention and Treatment of Nausea and Vomiting Induced by Chemotherapy of Lung Cancer
NCT03642457	PHASE4	TERMINATED	Efficacy Between Serratus Plane Block And Local Infiltration In Vats
NCT04145570	PHASE4	COMPLETED	A Single-Dose,ComparativeBioavailability Study ofTwo Formulations ofErlotinib150mgTabletsunderFastingConditions
NCT04155008	PHASE4	TERMINATED	Nutrition and Pharmacological Algorithm for Oncology Patients Study
NCT04613284	PHASE4	UNKNOWN	Rh-Endostatin Combined With CCRT(50 Gy) Followed by Durvalumab Maintenance for the Treatment of Specific Phase III NSCLC
NCT05463913	PHASE4	RECRUITING	Lung Nodule Detection Using Ultra-long FOV PET/CT
NCT05521789	PHASE4	RECRUITING	Erector Spinae Block for Thoracic Surgery
NCT05525338	PHASE4	RECRUITING	Comparison of Standard Dose Alectinib to Alectinib in Adjusted Dose Based on Alectinib Bloodlevels
NCT05663242	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Lung Tumors and Its Mechanism of Action
NCT05926336	PHASE4	RECRUITING	The Effects of Using Different Anesthetics on the Prognosis of Primary Tumors and Its Mechanism of Action
NCT06105801	PHASE4	RECRUITING	EBUS-TBNA vs Transbronchial Mediastinal Cryobiopsy for Adequacy of Next Generation Sequencing
NCT06276933	PHASE4	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	PHASE4	RECRUITING	PROspective Master-protocol for Evaluation of Systemic THErapeutics in Elderly With Thoracic Malignancies
NCT07405086	PHASE4	RECRUITING	Morning Versus Afternoon Administration of Immunotherapy for the Treatment of Advanced or Metastatic Solid Tumors, The Knight SHIFT Study
NCT00002550	PHASE3	COMPLETED	Chemotherapy Plus Radiation Therapy With or Without Surgery in Treating Patients With Stage IIIA Non-small Cell Lung Cancer
NCT00002583	PHASE3	COMPLETED	Vinorelbine + Cisplatin or No Further Therapy in Non-small Cell Lung Cancer That Has Been Surgically Removed
NCT00002623	PHASE3	COMPLETED	Chemotherapy Followed by Surgery or Radiation Therapy in Treating Patients With Stage III Non-small Cell Lung Cancer