CASP2

Summary

CASP2 (caspase 2, HGNC:1503) is a protein-coding gene on chromosome 7q34, encoding Caspase-2 (P42575). Is a regulator of the cascade of caspases responsible for apoptosis execution.

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Caspases mediate cellular apoptosis through the proteolytic cleavage of specific protein substrates. The encoded protein may function in stress-induced cell death pathways, cell cycle maintenance, and the suppression of tumorigenesis. Increased expression of this gene may play a role in neurodegenerative disorders including Alzheimer’s disease, Huntington’s disease and temporal lobe epilepsy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 835 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly (Moderate, GenCC)
• Clinical variants (ClinVar): 96 total — 4 pathogenic, 1 likely-pathogenic
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈3% of expected missense variation)
• GTEx eGene: eQTL in 14 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 25
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.94 (unconstrained)
• MANE Select transcript: NM_032982
• Notable: 96 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1503
Approved symbol	CASP2
Name	caspase 2
Location	7q34
Locus type	gene with protein product
Status	Approved
Aliases	ICH1, PPP1R57, MGC2181
Ensembl gene	ENSG00000106144
Ensembl biotype	protein_coding
OMIM	600639
Entrez	835

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000310447

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

ENST00000310447, ENST00000350623, ENST00000392925, ENST00000472067, ENST00000481483, ENST00000493642, ENST00000619992, ENST00000869939, ENST00000924441, ENST00000924442, ENST00001007260, ENST00001141255

RefSeq mRNA: 3 — MANE Select: NM_032982 NM_001224, NM_032982, NM_032983

CCDS: CCDS47733, CCDS5879

Canonical transcript exons

ENST00000310447 — 11 exons

Exon	Start	End
ENSE00001823824	143304940	143307696
ENSE00003492920	143300204	143300294
ENSE00003495249	143294230	143294324
ENSE00003547162	143292300	143292467
ENSE00003562605	143303784	143303933
ENSE00003600481	143292617	143292698
ENSE00003617737	143291540	143291690
ENSE00003640431	143294597	143294773
ENSE00003657309	143304674	143304783
ENSE00003657885	143299923	143300051
ENSE00003843516	143288351	143288529

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 97.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.7490 / max 149.2756, expressed in 1764 samples.

Highest expression (Bgee): buccal mucosa cell, tendon of biceps brachii, trabecular bone tissue, esophagus squamous epithelium, skin of hip.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CASP2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

16 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	2.3e-24	+0.85	7:143251680:A:G
Skin Sun Exposed Lower leg	eqtl	2.9e-04	-0.21	7:143138681:C:T
Skin Not Sun Exposed Suprapubic	eqtl	3.6e-04	+0.68	7:144276702:C:T
Spleen	eqtl	3.4e-03	+0.93	7:143251680:A:G
Pituitary	eqtl	5.9e-03	-0.39	7:143148457:G:A
Esophagus Mucosa	eqtl	1.2e-02	-0.11	7:142426136:T:A
Minor Salivary Gland	sqtl	2.0e-02	+3.29	7:142468207:G:T
Artery Coronary	eqtl	2.0e-02	+0.46	7:142989719:G:A
Nerve Tibial	eqtl	2.2e-02	+0.17	7:143197784:T:C
Lung	sqtl	2.3e-02	-0.49	7:143319902:T:A
Adipose Subcutaneous	eqtl	2.6e-02	+0.20	7:143289591:G:A
Breast Mammary Tissue	eqtl	3.0e-02	-0.48	7:143353240:C:T
Esophagus Muscularis	eqtl	3.7e-02	+0.34	7:142939774:G:A
Testis	eqtl	3.9e-02	+0.28	7:143289591:G:A
Thyroid	eqtl	4.7e-02	-0.22	7:143358482:G:C
Artery Tibial	eqtl	5.0e-02	+0.31	7:143042690:T:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
81763	8.0383	1698
81762	2.2095	1283
81765	0.5012	299

Top tissues by expression

showing 100 of 295 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	97.87	gold quality
tendon of biceps brachii	UBERON:0008188	96.12	gold quality
trabecular bone tissue	UBERON:0002483	91.51	gold quality
esophagus squamous epithelium	UBERON:0006920	90.56	gold quality
skin of hip	UBERON:0001554	90.45	gold quality
upper leg skin	UBERON:0004262	90.30	gold quality
tonsil	UBERON:0002372	90.09	gold quality
ganglionic eminence	UBERON:0004023	89.43	gold quality
blood	UBERON:0000178	89.25	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.11	gold quality
oral cavity	UBERON:0000167	89.08	gold quality
secondary oocyte	CL:0000655	88.91	gold quality
colonic mucosa	UBERON:0000317	88.61	gold quality
medial globus pallidus	UBERON:0002477	88.37	gold quality
epithelium of nasopharynx	UBERON:0001951	88.35	gold quality
mammary duct	UBERON:0001765	88.26	gold quality
mammalian vulva	UBERON:0000997	88.24	gold quality
granulocyte	CL:0000094	88.15	gold quality
nipple	UBERON:0002030	88.10	gold quality
lymph node	UBERON:0000029	87.84	gold quality
gingiva	UBERON:0001828	87.79	gold quality
ventricular zone	UBERON:0003053	87.53	gold quality
cortical plate	UBERON:0005343	87.51	gold quality
bone marrow	UBERON:0002371	87.49	gold quality
monocyte	CL:0000576	87.33	gold quality
pharyngeal mucosa	UBERON:0000355	87.32	gold quality
leukocyte	CL:0000738	87.23	gold quality
mononuclear cell	CL:0000842	86.93	gold quality
endometrium	UBERON:0001295	86.92	gold quality
gingival epithelium	UBERON:0001949	86.74	gold quality
jejunal mucosa	UBERON:0000399	86.71	gold quality
pigmented layer of retina	UBERON:0001782	86.58	gold quality
retina	UBERON:0000966	86.56	gold quality
visceral pleura	UBERON:0002401	86.56	gold quality
oocyte	CL:0000023	86.26	gold quality
parietal pleura	UBERON:0002400	86.12	gold quality
tibia	UBERON:0000979	86.08	gold quality
sural nerve	UBERON:0015488	86.03	gold quality
colonic epithelium	UBERON:0000397	85.95	gold quality
amniotic fluid	UBERON:0000173	85.82	gold quality
mucosa of transverse colon	UBERON:0004991	85.80	gold quality
penis	UBERON:0000989	85.70	gold quality
superior surface of tongue	UBERON:0007371	85.69	gold quality
pleura	UBERON:0000977	85.66	gold quality
mammary gland	UBERON:0001911	85.66	gold quality
lower lobe of lung	UBERON:0008949	85.66	gold quality
superficial temporal artery	UBERON:0001614	85.64	gold quality
placenta	UBERON:0001987	85.62	gold quality
thoracic mammary gland	UBERON:0005200	85.59	gold quality
spleen	UBERON:0002106	85.51	gold quality
adult organism	UBERON:0007023	85.35	gold quality
rectum	UBERON:0001052	85.32	gold quality
globus pallidus	UBERON:0001875	85.25	gold quality
skin of leg	UBERON:0001511	85.24	gold quality
epithelium of mammary gland	UBERON:0003244	85.20	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.06	gold quality
stromal cell of endometrium	CL:0002255	84.78	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.70	gold quality
mucosa of paranasal sinus	UBERON:0005030	84.70	gold quality
zone of skin	UBERON:0000014	84.68	gold quality
corpus epididymis	UBERON:0004359	84.65	gold quality
skin of abdomen	UBERON:0001416	84.59	gold quality
pylorus	UBERON:0001166	84.56	gold quality
esophagus mucosa	UBERON:0002469	84.46	gold quality
duodenum	UBERON:0002114	84.41	gold quality
bronchial epithelial cell	CL:0002328	84.36	gold quality
small intestine	UBERON:0002108	84.18	gold quality
urethra	UBERON:0000057	84.14	gold quality
lower esophagus mucosa	UBERON:0035834	84.05	gold quality
epithelium of esophagus	UBERON:0001976	83.88	gold quality
palpebral conjunctiva	UBERON:0001812	83.84	gold quality
vagina	UBERON:0000996	83.83	gold quality
mouth mucosa	UBERON:0003729	83.59	gold quality
subcutaneous adipose tissue	UBERON:0002190	83.24	gold quality
apex of heart	UBERON:0002098	83.20	gold quality
peripheral nervous system	UBERON:0000010	83.12	gold quality
nerve	UBERON:0001021	83.12	gold quality
tibial nerve	UBERON:0001323	83.12	gold quality
minor salivary gland	UBERON:0001830	83.12	gold quality
female reproductive system	UBERON:0000474	82.89	gold quality
trigeminal ganglion	UBERON:0001675	82.88	gold quality
renal medulla	UBERON:0000362	82.82	gold quality
transverse colon	UBERON:0001157	82.65	gold quality
ectocervix	UBERON:0012249	82.65	gold quality
saliva-secreting gland	UBERON:0001044	82.64	gold quality
right uterine tube	UBERON:0001302	82.50	gold quality
connective tissue	UBERON:0002384	82.40	gold quality
seminal vesicle	UBERON:0000998	82.38	gold quality
endocervix	UBERON:0000458	82.36	gold quality
germinal epithelium of ovary	UBERON:0001304	82.34	gold quality
adipose tissue	UBERON:0001013	82.32	gold quality
uterus	UBERON:0000995	82.27	gold quality
tendon	UBERON:0000043	82.23	gold quality
intestine	UBERON:0000160	82.23	gold quality
upper lobe of lung	UBERON:0008948	82.06	gold quality
caput epididymis	UBERON:0004358	81.93	gold quality
caecum	UBERON:0001153	81.89	gold quality
upper lobe of left lung	UBERON:0008952	81.74	gold quality
large intestine	UBERON:0000059	81.59	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.65
E-GEOD-76312	no	1402.28
E-GEOD-110499	no	611.48
E-CURD-112	no	2.39

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	37.9	medium
Thymus	tissue	25.6
Tonsil	tissue	25.3	medium
Cerebellum	tissue	21.0	high
Lymph node	tissue	20.5	high
Olfactory bulb	tissue	18.7
Skin 1	tissue	16.5	high
Corpus callosum	tissue	16.1
Basal ganglia	tissue	15.1	medium
Cerebral cortex	tissue	14.8	medium
Insular cortex	tissue	14.8
Amygdala	tissue	14.3
Ventral forebrain	tissue	14.1
Retrosplenial cortex	tissue	13.9
Septum	tissue	13.8
Spleen	tissue	13.5	high
Hippocampal formation	tissue	13.3
Putamen	tissue	13.1
Hypothalamus	tissue	13.1
Retrosplenial and cingulate cortex	tissue	13.1
Appendix	tissue	13.1	high
Temporal cortex	tissue	13.1
Periaqueductal gray	tissue	12.9
Substantia nigra	tissue	12.7
Prefrontal cortex	tissue	12.5
Spinal cord	tissue	12.5
Entorhinal cortex	tissue	12.5
Motor cortex	tissue	12.4
Somatosensory cortex	tissue	12.4
Choroid plexus	tissue	12.1
Occipital cortex	tissue	12.1
Rectum	tissue	11.9	high
Midbrain	tissue	11.8
Placenta	tissue	11.7	high
Nucleus accumbens	tissue	11.6
Medulla oblongata	tissue	11.6
Superior colliculi	tissue	11.4
Vagina	tissue	11.0	high
Thalamus	tissue	11.0
Pons	tissue	10.9
Parathyroid gland	tissue	10.5	medium
Colon	tissue	10.4	high
Cervix	tissue	10.1	high
Duodenum	tissue	10.1	medium
Breast	tissue	9.8	high
Fallopian tube	tissue	9.7	high
Endometrium 1	tissue	9.6	medium
Small intestine	tissue	9.5	high
Hippocampus	tissue	9.2	medium
Stomach 1	tissue	9.0	medium
Epididymis	tissue	9.0	medium
Ovary	tissue	8.8	medium
Smooth muscle	tissue	8.8	high
Postcentral gyrus	tissue	8.8
Locus coeruleus	tissue	8.7
Lung	tissue	8.6	medium
Salivary gland	tissue	8.5	low
Testis	tissue	8.4	high
Esophagus	tissue	8.1	medium
Thyroid gland	tissue	7.4	high

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Parieto-temporal junction (white matter) (18.2), Temporal white matter (17.6), White matter (16.1), Corpus callosum, genu (white matter) (16.0), Corpus callosum, splenium (white matter) (15.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, E2F1, FOXO1, PPARA, RUNX3, SREBF2, STAT1, TP53, TP73, XPC

miRNA regulators (miRDB)

Targeting CASP2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 118 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-7-1-3P	99.91	71.53	4384

Functional genomics

gnomAD constraint: pLI 1.74e-09, LOEUF 0.936, missense Z 1.45 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000310447 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈3% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
7:143,288,456–143,291,620	89 / 67.1	1.33	no
7:143,291,621–143,291,664	6 / 17.1	0.35	yes (p 7.4e-03)
7:143,291,665–143,305,068	417 / 495.4	0.84	no

Literature-anchored findings (GeneRIF, showing 40)

• role in cytochrome C release and apoptosis from the nucleus (PMID:11823470)
• Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. (PMID:11832478)
• acts upstream of mitochondria to promote cytochrome c release during etoposide-induced apoptosis (PMID:12065594)
• The long isoform of pro-CASP2 decreased first in mitochondria, then cytosol, then microsomes, and finally accumulated in the nucleus of U937 cells during TPA-induced differentiation. (PMID:12145703)
• cytotoxic stress causes activation of caspase-2, and this caspase is required for the permeabilization of mitochondria (PMID:12193789)
• caspase-2 gene: alternative promoters, pre-mRNA splicing and AUG usage direct isoform-specific expression (PMID:12584573)
• The short isoform is overexpressed in macrophage-derived foam cells of human atherosclerotic plaques (PMID:12598307)
• CASP2 expression was elevated upon RNF36 induction in test cells. (PMID:12837286)
• the x-ray structure of caspase-2 in complex with the inhibitor acetyl-Leu-Asp-Glu-Ser-Asp-aldehyde at 1.65-A resolution; the intersubunit disulfide bridge stabilizes the dimeric form (PMID:12920126)
• caspase 7 and caspase 8, but not caspase 2, are involved in induction of apoptosis by sphingosine (PMID:14584591)
• apoptosis was preceded by proteolytic cleavage of caspases 2, 3, and 7, and wild type STAT1 also induced cleavage of caspase 7 (PMID:14623896)
• Bax plays an important role in UV-induced apoptosis and in caspase-2 activation in tumor cells. (PMID:14647455)
• engineered a p53-mutant breast cancer cell line, Hs578T, to inducibly express HOXA5. Expression of HOXA5 can induce apoptosis through an apoptotic mechanism mediated by caspases 2 and 8. (PMID:14701762)
• Apoptosis signaling triggered by ascididemin is routed via CASP2 and JNK to mitochondria. (PMID:14716300)
• activation of caspase-2 occurs in a complex that contains PIDD, whose expression is induced by p53, and RAIDD; increased PIDD expression resulted in spontaneous activation of caspase-2 and sensitization to apoptosis by genotoxic stimuli (PMID:15073321)
• caspase-2 has a role in cleavage of Bid (PMID:15173176)
• caspase-2 and caspase-8 activation have roles in the mitochondrial apoptotic pathway induced by ceramide or etoposide (PMID:15262979)
• analysis of the biochemical mechanism of caspase-2 activation (PMID:15297885)
• caspase-2, -6 and -7 expression in gastric cancer cells is decreased compared to in normal gastric mucosal cells (PMID:15511269)
• glucocorticoid modulatory element-binding protein 1 (GMEB1) is capable of binding to the prodomain of caspase-2; GMEB1 may be an endogenous inhibitory protein that selectively interacts with prodomain of caspase-2 to disrupt the autoactivation (PMID:15555560)
• human casp2 CARD domain is sufficient for activation of NF-kB and p38 MAPK (PMID:15590671)
• Bcl-2-modulated caspase-2 activity occurred upstream of mitochondria (PMID:15817479)
• procaspase-2S-mediated anti-apoptotic effects are associated with inhibition of the processing and activation of procaspase-3 in VP-16-treated cells (PMID:15843892)
• proteolytic activation of Bid and the subsequent induction of the mitochondrial apoptotic pathway through Bax/Bak is essential for apoptosis triggered by caspase-2 (PMID:16172118)
• The activated caspase-2 processes procaspase-8 monomers between the large and small subunits, thereby priming cancer cells for TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. (PMID:16193064)
• CASP-2 gene is a member of the SREBP-responsive gene battery that senses lipid levels in cells and raise the possibility that caspase-2 participates in the control of cholesterol and triacylglycerol levels. (PMID:16227610)
• the function of an additional SREBP-1 responsive element located in the first intron of caspase-2 gene (PMID:16387548)
• analysis of novel mechanisms for apoptosis induction by silibinin involving p53-caspase 2 activation and caspase-mediated cleavage of Cip1/p21 (PMID:16777994)
• caspase-2 is activated at the DISC but does not play an initiating role in the CD95-induced apoptosis. (PMID:16822901)
• mechanistic studies identify a functional link between reactive oxygen specie and the caspase cascade involving caspase 2 and cleavage of BclXL (PMID:16843824)
• Caspase-9 is not only required for DeltaPsi(M) loss but also for caspase-2 activation, suggesting that these two events are downstream of the apoptosome (PMID:17079734)
• PIDD autoproteolysis marks the bifurcation between pro-death caspase-2 and pro-survival NF-kappaB pathway (PMID:17159900)
• Data show that histone deacetylase inhibition leads to decreased protein kinase casein kinase 2 activity, caspase-2 activation and partial cleavage of caspase-8 that sensitizes the tumor cell to TRAIL. (PMID:17195089)
• Data suggest that caspase 2-mediated programmed cell death participates in the seizure-induced degenerative process in experimental and human TLE. (PMID:17627033)
• PIDD isoforms are capable of activating nuclear factor-kappaB in response to genotoxic stress, but only isoform 1 interacts with RIP-associated ICH-1/CED-3 homologous protein with a death domain and activates caspase-2. (PMID:17637755)
• Interestingly, nuclear DNA fragmentation occurred and consistently DNA fragmentation factor (DFF45)/Inhibitor of caspase-activated DNase (ICAD) was cleaved inside the cell as well as in vitro, suggesting a role of caspase-2 in nuclear DNA fragmentation. (PMID:17945178)
• control of caspase-2 exon 9 inclusion by topoisomerase inhibitors depends on phosphorylation and/or dephosphorylation events, and on the cell cycle phase (PMID:18166155)
• p53-mediated apoptosis occurs by a PIDD- and caspase 2-dependent mechanism, and p53’s full transcriptional regulatory functions may be required only for events that are downstream of cytochrome c release (PMID:18238895)
• Although knockdown of c-Myc or caspase-2 does not affect Bax expression, caspase-2 is important for cytosolic Bax to integrate into the outer mitochondrial membrane, and c-Myc is critical for oligomerization of Bax once integrated into the membrane (PMID:18375382)
• Rottlerin induces down-regulation of caspase-2 via PKC delta-independent but ubiquitin proteasome-mediated pathway. (PMID:18413747)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp2	ENSDARG00000062052
mus_musculus	Casp2	ENSMUSG00000029863
rattus_norvegicus	Casp2	ENSRNOG00000016707
drosophila_melanogaster	Dronc	FBGN0026404
drosophila_melanogaster	Decay	FBGN0028381
caenorhabditis_elegans		WBGENE00000417
caenorhabditis_elegans		WBGENE00000820
caenorhabditis_elegans	csp-3	WBGENE00000821

Paralogs (16): CASP10 (ENSG00000003400), CFLAR (ENSG00000003402), CASP8 (ENSG00000064012), PYCARD (ENSG00000103490), CASP14 (ENSG00000105141), 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:97295) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 22 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cecum morphology	1
abnormal facial motor nucleus morphology	1
abnormal sympathetic neuron morphology	1
abnormal oocyte morphology	1
abnormal testis morphology	1
enlarged testis	1
persistence of hyaloid vascular system	1
cataract	1
abnormal retina morphology	1
increased startle reflex	1
abnormal apoptosis	1
abnormal skin morphology	1
abnormal kidney morphology	1
abnormal brain morphology	1
abnormal vitreous body morphology	1
small kidney	1
abnormal neuron apoptosis	1
increased brain size	1
abnormal female germ cell morphology	1
abnormal B cell apoptosis	1
enlarged cecum	1
increased primordial ovarian follicle number	1

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
Pongo abelii	Q5R6I4	98.5%	Diamond
Macaca fascicularis	Q2PFV2	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
Bos taurus	Q3T0P5	88.3%	Diamond
Caenorhabditis remanei	P45436	84.5%	Diamond
Xenopus laevis	P55865	79.5%	Diamond
Gallus gallus	F1NV61	73.9%	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
TMEM139	protein-coding	135932
TAS2R40	protein-coding	259286
GSTK1	protein-coding	373156
TMEM139-AS1	ncRNA	105375545
CLCN1	protein-coding	1180
FAM131B-AS2	ncRNA	100507507
FAM131B-AS1	ncRNA	101928397
FAM131B	protein-coding	9715

Protein

Protein identifiers

Caspase-2 — P42575 (reviewed: P42575)

Alternative names: Neural precursor cell expressed developmentally down-regulated protein 2, Protease ICH-1

All UniProt accessions (4): A0A087WYM1, A0A0S2Z3H1, C9JRR9, P42575

UniProt curated annotations — full annotation on UniProt →

Function. Is a regulator of the cascade of caspases responsible for apoptosis execution. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival. Associates with PIDD1 and CRADD to form the PIDDosome, a complex that activates CASP2 and triggers apoptosis in response to genotoxic stress. Acts as a positive regulator of apoptosis. Acts as a negative regulator of apoptosis. May function as an endogenous apoptosis inhibitor that antagonizes caspase activation and cell death.

Subunit / interactions. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a p18 subunit and a p12 subunit. Forms a complex named the PIDDosome with PIDD1 and CRADD. Interacts with NOL3 (via CARD domain); inhibits CASP2 activity in a phosphorylation-dependent manner.

Tissue specificity. Expressed at higher levels in the embryonic lung, liver and kidney than in the heart and brain. In adults, higher level expression is seen in the placenta, lung, kidney, and pancreas than in the heart, brain, liver and skeletal muscle.

Post-translational modifications. The mature protease can process its own propeptide, but not that of other caspases.

Disease relevance. Intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly (MRT80) [MIM:620653] An autosomal recessive disorder characterized by global developmental delay, mildly to moderately impaired intellectual development, attention deficit-hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. Brain imaging shows fronto-temporal lissencephaly and pachygyria. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The CARD domain mediates a direct interaction with CRADD.

Similarity. Belongs to the peptidase C14A family.

Isoforms (3)

UniProt ID	Names	Canonical?
P42575-1	1, ICH-1L	yes
P42575-2	2, ICH-1S
P42575-3	3, Casp-2L-Pro

RefSeq proteins (3): NP_001215, NP_116764, NP_116765 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001309	Pept_C14_p20	Domain
IPR001315	CARD	Domain
IPR002138	Pept_C14_p10	Domain
IPR002398	Pept_C14	Family
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
IPR035702	CASP2_CARD	Domain

Pfam: PF00619, PF00656

Enzyme classification (BRENDA)

• EC 3.4.22.55 — caspase-2 (BRENDA: 7 organisms, 149 substrates, 54 inhibitors, 18 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ABZ-VDVADFA-DAP(DNP)	0.058–0.079	3
ABZ-VDVADGA-DAP(DNP)	0.049–0.112	3
ABZ-VDVADQA-DAP(DNP)	0.114–0.128	3
ABZ-VDVADVA-DAP(DNP)	0.064–0.086	3
ABZ-VDVADPA-DAP(DNP)	0.152–0.305	2
AC-VDVAD-7-AMIDO-4-TRIFLUOROMETHYLCOUMARIN	0.025	1
ACETYL-VDQQD-4-NITROANILIDE	0.53	1
ACETYL-VDVAD-4-NITROANILIDE	0.053	1
ACETYL-VDVADGW-AMIDE	0.15	1

UniProt features (67 total): strand 14, helix 13, mutagenesis site 9, sequence variant 6, splice variant 5, turn 5, modified residue 3, chain 3, propeptide 2, active site 2, initiator methionine 1, sequence conflict 1, domain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

17 structures by resolution:

PDB	Title	Method	Resolution (Å)
6Y8D	14-3-3 Sigma in complex with phosphorylated caspase{pS164} peptide	X-RAY DIFFRACTION	1.51
8VP4	Crystal Structure of JF1cpCasp2 with Peptide Inhibitor AcVDVAD-CHO	X-RAY DIFFRACTION	1.51
6Y8B	14-3-3 Sigma in complex with phosphorylated caspase{pS139} peptide	X-RAY DIFFRACTION	1.54
6S9K	Structure of 14-3-3 gamma in complex with caspase-2 peptide containing 14-3-3 binding …	X-RAY DIFFRACTION	1.6
1PYO	Crystal Structure of Human Caspase-2 in Complex with Acetyl-Leu-Asp-Glu-Ser-Asp-cho	X-RAY DIFFRACTION	1.65
3R5J	Crystal structure of active caspase-2 bound with Ac-ADVAD-CHO	X-RAY DIFFRACTION	1.77
3R7B	Caspase-2 bound to one copy of Ac-DVAD-CHO	X-RAY DIFFRACTION	1.8
3R6L	Caspase-2 T380A bound with Ac-VDVAD-CHO	X-RAY DIFFRACTION	1.9
9C2Y	Crystal Structure of JF1cpCasp2 in complex with MUR-65	X-RAY DIFFRACTION	1.96
3R6G	Crystal structure of active caspase-2 bound with Ac-VDVAD-CHO	X-RAY DIFFRACTION	2.07
3R7S	Crystal Structure of Apo Caspase2	X-RAY DIFFRACTION	2.25
3R7N	Caspase-2 bound with two copies of Ac-DVAD-CHO	X-RAY DIFFRACTION	2.33
3RJM	CASPASE2 IN COMPLEX WITH CHDI LIGAND 33c	X-RAY DIFFRACTION	2.55
6GKF	Structure of 14-3-3 gamma in complex with caspase-2 14-3-3 binding motif Ser139	X-RAY DIFFRACTION	2.6
6SAD	Structure of 14-3-3 gamma in complex with double phosphorylated caspase-2 peptide on …	X-RAY DIFFRACTION	2.75
6GKG	Structure of 14-3-3 gamma in complex with caspase-2 14-3-3 binding motif Ser164	X-RAY DIFFRACTION	2.85
2P2C	Inhibition of caspase-2 by a designed ankyrin repeat protein (DARPin)	X-RAY DIFFRACTION	3.24

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42575-F1	78.95	0.53

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Peptidases, Cysteine-type peptidases, Predicted intracellular proteins, Plasma proteins, Cancer-related genes, Candidate cancer biomarkers

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria

Antibody reliability (HPA): IH approved · IF supported

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 (2)

Position	Role
320
277

Post-translational modifications (3)

Type	Positions
N-acetylalanine	2
Phosphoserine	157, 340

Mutagenesis-validated functional residues (9)

Position	Phenotype
57	loss of interaction with cradd.
95	loss of interaction with cradd.
99	loss of interaction with cradd.
100	no effect on interaction with cradd. loss of interaction with cradd; when associated a-104.
102	loss of interaction with cradd.
104	no effect on interaction with cradd. loss of interaction with cradd; when associated a-100.
106	loss of interaction with cradd.
320	loss of function.
369	loss of function.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 15; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

15 pathways:

ID	Pathway	Evidence
R-HSA-205025	NADE modulates death signalling	curated
R-HSA-168638	NOD1/2 Signaling Pathway	curated
R-HSA-6803207	TP53 Regulates Transcription of Caspase Activators and Caspases	curated
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE	—
R-HSA-73887	Death Receptor Signaling	—
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-168643	Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	—
R-HSA-73857	RNA Polymerase II Transcription	—
R-HSA-162582	Signal Transduction	—
R-HSA-5633008	TP53 Regulates Transcription of Cell Death Genes	—
R-HSA-3700989	Transcriptional Regulation by TP53	—
R-HSA-193704	p75 NTR receptor-mediated signalling	—

MSigDB gene sets: 348 (showing top): MORF_RAGE, MODULE_52, E2F_Q4_01, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_NOD1_2_SIGNALING_PATHWAY, FISCHER_G1_S_CELL_CYCLE, TGCACTT_MIR519C_MIR519B_MIR519A, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GCAAGGA_MIR502, GOBP_EXTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_NEURAL_RETINA_DEVELOPMENT, MODULE_16, BAKER_HEMATOPOESIS_STAT1_TARGETS

GO Biological Process (17): luteolysis (GO:0001554), neural retina development (GO:0003407), apoptotic process (GO:0006915), DNA damage response (GO:0006974), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), protein processing (GO:0016485), DNA damage response, signal transduction by p53 class mediator (GO:0030330), positive regulation of apoptotic process (GO:0043065), negative regulation of apoptotic process (GO:0043066), positive regulation of neuron apoptotic process (GO:0043525), cellular response to mechanical stimulus (GO:0071260), apoptotic signaling pathway (GO:0097190), extrinsic apoptotic signaling pathway in absence of ligand (GO:0097192), execution phase of apoptosis (GO:0097194), proteolysis (GO:0006508), regulation of apoptotic process (GO:0042981), protein maturation (GO:0051604)

GO Molecular Function (10): cysteine-type endopeptidase activity (GO:0004197), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), identical protein binding (GO:0042802), protease binding (GO:0002020), protein binding (GO:0005515), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), death domain binding (GO:0070513)

GO Cellular Component (5): nucleus (GO:0005634), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

12 top-level categories:

Category	Pathways
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
Cell death signalling via NRAGE, NRIF and NADE	1
TP53 Regulates Transcription of Cell Death Genes	1
Immune System	1
Innate Immune System	1
Death Receptor Signaling	1
p75 NTR receptor-mediated signalling	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Transcriptional Regulation by TP53	1
Gene expression (Transcription)	1
Signal Transduction	1

GO top-level categories

48 GO namespaces:

Category	Terms
apoptotic process	5
protein binding	3
regulation of apoptotic process	2
protein metabolic process	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
female gonad development	1
ovulation cycle process	1
retina development in camera-type eye	1
animal gross anatomical part developmental process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
DNA damage response	1
intrinsic apoptotic signaling pathway	1
proteolysis	1
protein maturation	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
positive regulation of programmed cell death	1
negative regulation of programmed cell death	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
signal transduction	1
signal transduction in absence of ligand	1
extrinsic apoptotic signaling pathway	1
cellular process	1
bleb assembly	1
regulation of programmed cell death	1
gene expression	1
endopeptidase activity	1
cysteine-type peptidase activity	1
enzyme binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
protein domain specific binding	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 32 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
DNA damage response, signal transduction by p53 class mediator	BP	mutant phenotype
cellular response to mechanical stimulus	BP	expression pattern
positive regulation of apoptotic process	BP	direct assay
protein processing	BP	direct assay
mitochondrion	CC	direct assay
cysteine-type endopeptidase activity	MF	direct assay
identical protein binding	MF	physical interaction
protein domain specific binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,242 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP2	PIDD1	Q9HB75	941
CASP2	CRADD	P78560	936
CASP2	CYCS	P00001	829
CASP2	FADD	Q13158	750
CASP2	TP53	P04637	730
CASP2	BAX	P55269	719
CASP2	MZB1	Q8WU39	717
CASP2	APAF1	O14727	715
CASP2	TRADD	Q15628	711
CASP2	NEDD1	Q8NHV4	702
CASP2	DIABLO	Q9NR28	684
CASP2	BCL2	P10415	678
CASP2	XIAP	P98170	659
CASP2	ITGB3BP	Q13352	655
CASP2	TNFRSF1A	P19438	643

IntAct

Human interaction partners of CASP2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

13 partners by confidence:

Partner	Interaction type	MIscore	Records
CRADD	physical association	0.970	32
PIDD1	association	0.630	2
BAG4	physical association	0.560	3
CAF40	physical association	0.560	3
PRKAB2	physical association	0.560	3
MDM2	protein cleavage	0.440	2
PDS5B	physical association	0.400	1
EEF1A1	physical association	0.370	1
GRB2	physical association	0.370	1
RAI1	physical association	0.370	1
RPL30	physical association	0.370	1
RXRA	physical association	0.370	1
SPG11	physical association	0.370	1

BioGRID (91 interactions; top human partners by supporting records): CRADD (Two-hybrid; 12 records), CIB1 (Two-hybrid; 4 records), PIDD1 (Affinity Capture-Western; 4 records), BBOX1 (Affinity Capture-MS; 3 records), EPN3 (Affinity Capture-MS; 3 records), RFXANK (Two-hybrid; 3 records), TRAF2 (Affinity Capture-MS; 3 records), BID (Biochemical Activity; 2 records), BIRC2 (Affinity Capture-MS; 2 records), CASP3 (Biochemical Activity; 2 records), CASP8 (Biochemical Activity; 2 records), HNRNPK (Affinity Capture-MS; 2 records), TRAF1 (Affinity Capture-MS; 2 records), TRAF3 (Affinity Capture-MS; 2 records), AGO2 (Affinity Capture-RNA)

SIGNOR signaling

11 signaling interactions:

A	Effect	B	Mechanism
CSNK2A1	down-regulates	CASP2	phosphorylation
BIRC2	down-regulates	CASP2	binding
PRKDC	up-regulates	CASP2	phosphorylation
RUNX3	“up-regulates quantity by expression”	CASP2	“transcriptional regulation”
CASP2	“form complex”	“Caspase-2 PIDDosome”	binding
AURKB	“up-regulates activity”	CASP2	phosphorylation
PPP1CC	“up-regulates activity”	CASP2	dephosphorylation
PPP1CA	“up-regulates activity”	CASP2	dephosphorylation
PPP1CB	“up-regulates activity”	CASP2	dephosphorylation
CASP2	“form complex”	“Caspase 2 complex”	binding
PP1	“up-regulates activity”	CASP2	dephosphorylation

Protein complexes (CORUM) (1)

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

1 complexes by size:

Complex	Subunits	Members
PIDDsome complex	3	CASP2, CRADD, PIDD1

Disease & clinical

Genetic variants

Variant evidence for CASP2: 96 ClinVar records (5 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	47
Likely benign	14
Benign	2

Top pathogenic / likely-pathogenic (5)

Showing all 5 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
2499469	NM_032982.4(CASP2):c.1156del (p.Tyr386fs)	Pathogenic	criteria provided, single submitter	2
2499470	NM_032982.4(CASP2):c.1174C>T (p.Gln392Ter)	Pathogenic	criteria provided, single submitter	2
2499471	NM_032982.4(CASP2):c.130C>T (p.Arg44Ter)	Pathogenic	criteria provided, single submitter	2
2499511	NM_032982.4(CASP2):c.876+1G>T	Pathogenic	criteria provided, single submitter	2
985938	NM_032982.4(CASP2):c.560_561del (p.His187fs)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore CASP2’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; 43 predictions of 787):

Position(s)	Effect	Δscore	Sites
7:143288530–143288531	donor_loss	1.0000	5
7:143291538–143291539	acceptor_loss	1.0000	5
7:143291691–143291692	donor_loss	1.0000	4
7:143292298–143292299	acceptor_loss	1.0000	6
7:143292421	donor_gain	1.0000
7:143292468–143292469	donor_loss	1.0000	4
7:143299921–143299922	acceptor_loss	1.0000	5
7:143300052–143300053	donor_loss	1.0000	5
7:143300198–143300199	acceptor_gain	1.0000	2
7:143300202–143300203	acceptor_loss	1.0000	6

AlphaMissense

915 missense substitutions predicted likely pathogenic (of 2,983 scored), across 223 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M32	9	0.856	0.977
M70	9	0.829	0.926
H277	8	0.985	0.996
D225	8	0.980	0.991
D363	8	0.976	0.996
D326	8	0.947	0.978
F210	8	0.934	0.995
M432	8	0.929	0.975
N379	8	0.909	0.994
F102	8	0.898	0.992
F315	8	0.886	0.995
F300	8	0.868	0.979
F233	8	0.815	0.961
W385	7	0.992	0.998
C320	7	0.978	0.994
F426	7	0.965	0.993
F446	7	0.956	0.982
F99	7	0.944	0.979
N411	7	0.936	0.988
D287	7	0.923	0.970

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000114

Disease associations

OMIM: gene MIM:600639 | disease phenotypes: MIM:620653

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly	Moderate	Autosomal recessive	2

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (8 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

8 panels:

Panel	Rating
Cerebral malformation	green
DDG2P	green
Fetal anomalies	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Malformations of cortical development	green
Paediatric disorders	green

Mondo (1): intellectual developmental disorder, autosomal recessive 80, with variant lissencephaly (MONDO:0957999)

HPO phenotypes

25 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000219	Thin upper lip vermilion
HP:0000238	Hydrocephalus
HP:0000358	Posteriorly rotated ears
HP:0000582	Upslanted palpebral fissure
HP:0000648	Optic atrophy
HP:0000664	Synophrys
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001302	Pachygyria
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0002376	Developmental regression
HP:0005274	Prominent nasal tip
HP:0007018	Attention deficit hyperactivity disorder
HP:0007933	Broad lateral eyebrow
HP:0009905	Thin ear helix
HP:0010751	Dimple chin
HP:0011463	Childhood onset

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3831289 (PROTEIN FAMILY), CHEMBL4884 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C14: Caspase

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 4 [PMID: 12408711]	Inhibition	6.02	pKi

Binding affinities (BindingDB)

64 measured of 76 human assays (77 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[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
[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
(3S)-3-[(2S)-6-(6-{5-[(3aS,6aR)-2-oxo-hexahydro-1H-thieno[3,4-d]imidazolidin-4-yl]pentanamido}hexanamido)-2-[(2S)-2-{[(benzyloxy)carbonyl]amino}-4-carboxybutanamido]hexanamido]-5-[(2,6-dimethylphenyl)carbonyloxy]-4-oxopentanoic acid	KI	6.3 nM
CHEMBL1091826	EC50	16 nM
CHEMBL2323966	IC50	20 nM
CHEMBL1835324	IC50	22 nM
CHEMBL2324340	IC50	26 nM
CHEMBL1835210	IC50	41 nM
CHEMBL1835399	IC50	50 nM
CHEMBL1835211	IC50	108 nM
CHEMBL1835320	IC50	136 nM
CHEMBL1835321	IC50	150 nM
5-{[(4-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}phenyl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	160 nM
CHEMBL1835403	IC50	163 nM
4-oxo-4-(piperidin-1-yl)-N-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)butanamide	IC50	231 nM
WO2005113580-Ex-02	EC50	231 nM	WO-2005113580: ANTICORONVIRAL COMPOUNDS AND COMPOSITIONS, THEIR PHARMACEUTICAL USES AND MATERIALS FOR THEIR SYNTHESIS
2-oxo-1-phenyl-2-[(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]ethyl acetate	IC50	233 nM
CHEMBL1835313	IC50	413 nM
CHEMBL1835318	IC50	441 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
N-(1,3,4-Trioxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-succinamic acid	IC50	859 nM
CHEMBL2324341	IC50	1050 nM
CHEMBL1835322	IC50	1120 nM
CHEMBL1835209	IC50	1330 nM
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]pyridin-2-ylmethyl}sulfamoyl)-2-hydroxy-benzoic Acid	KI	1500 nM
1,2,3,4-tetrahydroisoquinoline-1,3,4-trione	IC50	1530 nM
CHEMBL1835319	IC50	1600 nM
CHEMBL1835208	IC50	1690 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
CHEMBL1835400	IC50	2190 nM
CHEMBL1835317	IC50	2360 nM
Heterocyclic deriv. 69b	KI	2700 nM
CHEMBL2324339	IC50	2700 nM
CHEMBL1835404	IC50	3110 nM
Thiophene Scaffold 66b	KI	3200 nM
Pyridine Scaffold 4	KI	3900 nM
Grassystatin A	IC50	5000 nM
CHEMBL1835325	IC50	5530 nM
N-(1,2,3,4-Tetrahydro-1,3,4-trioxoisoquinolin-7-yl)-4-nitrobenzamide	IC50	5670 nM
CETYLPYRIDINIUM BROMIDE	IC50	6000 nM
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]thiazol-2-hydroxy-benzoic Acidylmethyl}sulfamoyl)-2-	KI	8300 nM
5-(pyrrolidine-1-sulfonyl)-2,3-dihydro-1H-indole-2,3-dione	KI	9000 nM
1-methyl-5-nitro-2,3-dihydro-1H-indole-2,3-dione	KI	12000 nM
5-({(5-{[(2S)-1-carboxy-4-{[(2-chlorophenyl)methyl]sulfanyl}-3-oxobutan-2-yl]carbamoyl}thiophen-2-yl)methylamino}methyl)-2-hydroxybenzoic acid	KI	12000 nM
CHEMBL1835212	IC50	12600 nM
CHEMBL1835401	IC50	12800 nM
CHEMBL2323967	IC50	13200 nM
CHEMBL1835316	IC50	17400 nM

ChEMBL bioactivities

62 potent at pChembl≥5 of 88 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.46	Ki	3.5	nM	CHEMBL5641709
7.80	EC50	16	nM	CHEMBL1091826
7.66	IC50	22	nM	CHEMBL1835324
7.39	IC50	41	nM	CHEMBL1835208
7.39	IC50	41	nM	CHEMBL1835210
7.34	IC50	46	nM	CHEMBL1835209
7.32	IC50	47.86	nM	CHEMBL5641709
7.30	IC50	50	nM	CHEMBL1835317
7.30	IC50	50	nM	CHEMBL1835399
7.22	IC50	60	nM	CHEMBL1835325
7.07	IC50	86	nM	CHEMBL1835322
6.97	IC50	108	nM	CHEMBL1835211
6.87	IC50	136	nM	CHEMBL1835320
6.82	IC50	150	nM	CHEMBL1835321
6.79	IC50	163	nM	CHEMBL1835403
6.66	IC50	219	nM	CHEMBL1835316
6.64	IC50	231	nM	CHEMBL438969
6.63	IC50	233	nM	CHEMBL439872
6.61	IC50	246	nM	CHEMBL1835212
6.38	IC50	413	nM	CHEMBL1835313
6.36	IC50	441	nM	CHEMBL1835318
6.34	IC50	453	nM	CHEMBL1835314
6.34	IC50	459	nM	CHEMBL1835402
6.28	IC50	530	nM	CHEMBL382481
6.27	IC50	537	nM	CHEMBL203709
6.24	IC50	573	nM	CHEMBL1835404
6.20	IC50	635	nM	CHEMBL1835210
6.11	IC50	772	nM	CHEMBL1835315
6.11	IC50	781	nM	CHEMBL1835321
6.07	IC50	859	nM	CHEMBL202971
6.02	Ki	960	nM	CHEMBL358725
5.97	IC50	1072	nM	CHEMBL4779058
5.95	IC50	1120	nM	CHEMBL1835322
5.89	IC50	1288	nM	CHEMBL5647319
5.88	IC50	1334	nM	CHEMBL1835209
5.82	IC50	1530	nM	CHEMBL206435
5.80	IC50	1600	nM	CHEMBL1835319
5.77	IC50	1700	nM	CHEMBL5715925
5.77	IC50	1690	nM	CHEMBL1835208
5.74	IC50	1820	nM	CHEMBL5641655
5.71	IC50	1940	nM	CHEMBL1835211
5.70	IC50	1980	nM	CHEMBL1835401
5.66	IC50	2190	nM	CHEMBL1835400
5.65	IC50	2260	nM	CHEMBL1835324
5.63	IC50	2360	nM	CHEMBL1835317
5.51	IC50	3110	nM	CHEMBL1835404
5.50	IC50	3162	nM	CHEMBL5642543
5.48	IC50	3311	nM	CHEMBL4779058
5.47	IC50	3388	nM	CHEMBL5641655
5.40	Ki	4000	nM	CHEMBL439753

PubChem BioAssay actives

72 with measured affinity, of 230 total; 44 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
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-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(1S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.0220	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-3-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.0410	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S)-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.0410	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.0460	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	2140037: Inhibition of recombinant cp-caspase-2 (unknown origin) using Z-VDVAD-AFC as substrate measured after 40 mins by fluorescence assay	ic50	0.0479	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3S)-3-(2,2-dimethylpropyl)-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.0500	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-6-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.0500	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-7-methyl-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.0600	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S)-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]piperidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.0860	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3S)-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3-methoxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.1080	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3R)-3-cyclohexyl-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.1360	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-1,3-dihydroisoindol-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.1500	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[6-bromo-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.1630	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3S)-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3-pyrimidin-2-yloxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.2190	uM
4-oxo-4-piperidin-1-yl-N-(1,3,4-trioxoisoquinolin-6-yl)butanamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.2310	uM
[2-oxo-1-phenyl-2-[(1,3,4-trioxoisoquinolin-5-yl)amino]ethyl] acetate	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.2330	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3S)-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3-propan-2-yloxypyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.2460	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3S)-3-butan-2-yloxy-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.4130	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3R)-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3-phenylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.4410	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3S)-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3-(2-methylpropoxy)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.4530	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[7-hydroxy-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.4590	uM
3-chloro-N-(1,3,4-trioxoisoquinolin-6-yl)propanamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.5300	uM
N’-(2-methoxyphenyl)-N-(1,3,4-trioxoisoquinolin-6-yl)butanediamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.5370	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[7-bromo-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.5730	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3S)-3-cyclopentyloxy-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	0.7720	uM
4-oxo-4-[(1,3,4-trioxoisoquinolin-6-yl)amino]butanoic acid	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.8590	uM
5-[[5-[[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl]-2-pyridinyl]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	0.9600	uM
4-(2-chloroacetyl)-1,3-dihydroquinoxalin-2-one	2140027: Inhibition of recombinant caspase-2 (unknown origin) using Z-VDVAD-AFC as substrate measured after 40 mins by fluorescence assay	ic50	1.0715	uM
N-[4-[(2-chloroacetyl)amino]phenyl]thiophene-2-carboxamide	2140027: Inhibition of recombinant caspase-2 (unknown origin) using Z-VDVAD-AFC as substrate measured after 40 mins by fluorescence assay	ic50	1.2882	uM
isoquinoline-1,3,4-trione	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	1.5300	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[(2S,3R)-2-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3-(4-methylphenyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	1.6000	uM
2-chloro-1-[5-(2-methyl-1,3-thiazol-4-yl)-2,3-dihydroindol-1-yl]ethanone	2140027: Inhibition of recombinant caspase-2 (unknown origin) using Z-VDVAD-AFC as substrate measured after 40 mins by fluorescence assay	ic50	1.8197	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[6-hydroxy-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	1.9800	uM
(3S)-3-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-4-[[(2S)-1-[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	623155: Inhibition of caspase-2 (amino acids 170 to 452) using Ac-VDVAD-AMC coumarin-120 as substrate after 20 mins by fluorometric analysis	ic50	2.1900	uM
7-bromo-4-(2-chloroacetyl)-1-methyl-3H-quinoxalin-2-one	2140027: Inhibition of recombinant caspase-2 (unknown origin) using Z-VDVAD-AFC as substrate measured after 40 mins by fluorescence assay	ic50	3.1623	uM
1-benzyl-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	4.0000	uM
5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl-1H-indole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	4.9000	uM
methyl (2S)-1-[(2R)-2-[[(2S)-2-[[(2S,3R)-2-[[(3S,4S)-4-[[(2S)-4-amino-2-[[(2S)-2-[[(2R)-2-[(2S)-2-[(2S)-2-(dimethylamino)-3-methylbutanoyl]oxy-3-methylbutanoyl]oxy-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-3-hydroxy-6-methylheptanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]-methylamino]-3-phenylpropanoyl]pyrrolidine-2-carboxylate	448860: Inhibition of caspase 2 after 10 to 15 mins by fluorescence assay	ic50	5.0000	uM
2-chloro-N-(6-methoxy-1,3-benzothiazol-2-yl)acetamide	2140027: Inhibition of recombinant caspase-2 (unknown origin) using Z-VDVAD-AFC as substrate measured after 40 mins by fluorescence assay	ic50	5.2481	uM
4-nitro-N-(1,3,4-trioxoisoquinolin-7-yl)benzamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	5.6700	uM
5-[(2S)-2-(anilinomethyl)pyrrolidin-1-yl]sulfonyl-1H-indole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	6.5000	uM
N,N’-bis(3-aminopropyl)butane-1,4-diamine	328670: Activation of procaspase 2 after 24 hrs	ec50	8.5000	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	9.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects folding, decreases reaction, increases activity, increases cleavage, affects reaction (+3 more)	6
benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone	decreases reaction, increases activity, increases cleavage, increases reaction, decreases activity (+1 more)	5
Doxorubicin	increases response to substance, affects reaction, increases expression, increases splicing, decreases reaction (+3 more)	4
bisphenol A	affects expression, decreases expression, increases expression, affects cotreatment	3
sodium arsenite	increases cleavage, decreases expression	3
1-(2-chlorobenzyl)-5’-phenyl-3’H-spiro(indoline-3,2’-(1,3,4)thiadiazol)-2-one	increases activity, affects reaction	3
Bortezomib	increases reaction, affects reaction, increases response to substance, decreases reaction, increases activity (+1 more)	3
Estradiol	affects expression, decreases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
NOC 18	decreases expression	2
goniothalamin	increases activity	2
pifithrin	increases activity, increases cleavage, increases reaction, decreases reaction	2
Docetaxel	increases activity, increases cleavage	2
Arsenic Trioxide	increases expression	2
Arsenic	increases expression	2
Caffeine	decreases reaction, increases activity, increases cleavage, increases phosphorylation	2
Cisplatin	increases cleavage, increases expression, increases reaction	2
Diclofenac	decreases reaction, increases activity, affects expression	2
Hydrogen Peroxide	affects cotreatment, increases expression, increases activity	2
Tunicamycin	decreases reaction, increases activity, decreases expression	2
Staurosporine	increases cleavage	2
gardenin B	increases activity, increases cleavage	1
moringin	increases expression, affects cotreatment	1
nano-diamino-tetrac	decreases reaction, increases expression	1
dicrotophos	increases expression	1
naringenin	affects cotreatment, increases expression	1
benoxinate	increases activity	1
propylparaben	increases expression	1
diepoxybutane	increases expression	1
sodium cyanate	affects cotreatment, increases activity	1

ChEMBL screening assays

53 unique, capped per target: 48 binding, 2 admet, 2 functional, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4199992	Binding	Activation of caspase (unknown origin)	MK-8353: Discovery of an Orally Bioavailable Dual Mechanism ERK Inhibitor for Oncology. — *ACS Med Chem Lett*
CHEMBL4703757	ADMET	Inhibition of human Caspase 2	Discovery of Ketone-Based Covalent Inhibitors of Coronavirus 3CL Proteases for the Potential Therapeutic Treatment of COVID-19. — *J Med Chem*
CHEMBL5627057	Toxicity	Inhibition of human caspase 2 at 100 uM relative to control	Discovery and structure-activity relationship studies of novel α-ketoamide derivatives targeting the SARS-CoV-2 main protease. — *Eur J Med Chem*

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1LW	Abcam K-562 CASP2 KO	Cancer cell line	Female
CVCL_D2IG	Abcam Raji CASP2 KO	Cancer cell line	Male
CVCL_SG90	HAP1 CASP2 (-) 1	Cancer cell line	Male
CVCL_SG91	HAP1 CASP2 (-) 2	Cancer cell line	Male
CVCL_SG92	HAP1 CASP2 (-) 3	Cancer cell line	Male
CVCL_UQ28	Abcam Jurkat CASP2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CASP2 across ~30M SureChEMBL compounds — explore on Sugi Predict.