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): 91 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 25
• Druggable target: yes
• MANE Select transcript: NM_032982

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: 10 — 6 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

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

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.

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

295 total, 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

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

Regulation

Is transcription factor: no

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

miRNA regulators (miRDB)

118 targeting CASP2, 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-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

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)

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): P42575, A0A087WYM1, A0A0S2Z3H1, C9JRR9

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 (61 total): strand 12, helix 10, mutagenesis site 9, sequence variant 6, splice variant 5, turn 4, 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.

PDB	Method	Resolution (Å)
6Y8D	X-RAY DIFFRACTION	1.51
8VP4	X-RAY DIFFRACTION	1.51
6Y8B	X-RAY DIFFRACTION	1.54
6S9K	X-RAY DIFFRACTION	1.6
1PYO	X-RAY DIFFRACTION	1.65
3R5J	X-RAY DIFFRACTION	1.77
3R7B	X-RAY DIFFRACTION	1.8
3R6L	X-RAY DIFFRACTION	1.9
9C2Y	X-RAY DIFFRACTION	1.96
3R6G	X-RAY DIFFRACTION	2.07
3R7S	X-RAY DIFFRACTION	2.25
3R7N	X-RAY DIFFRACTION	2.33
3RJM	X-RAY DIFFRACTION	2.55
6GKF	X-RAY DIFFRACTION	2.6
6SAD	X-RAY DIFFRACTION	2.75
6GKG	X-RAY DIFFRACTION	2.85
2P2C	X-RAY DIFFRACTION	3.24

Predicted structure (AlphaFold)

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

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): 320; 277

Post-translational modifications (3): 2, 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

15 pathways

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

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 (19): 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), ectopic germ cell programmed cell death (GO:0035234), 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), positive regulation of apoptotic signaling pathway (GO:2001235), 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), cytosol (GO:0005829), endopeptidase complex (GO:1905369)

Reactome top-level categories

Rollup of top-12 pathways:

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

Rollup of top GO terms by namespace:

Category	Terms
apoptotic process	5
protein binding	3
apoptotic signaling pathway	2
regulation of apoptotic process	2
positive regulation of apoptotic process	2
protein metabolic process	2
cellular anatomical structure	2
female gonad development	1
ovulation cycle process	1
anatomical structure development	1
retina development in camera-type eye	1
programmed cell death	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
developmental process involved in reproduction	1
programmed cell death involved in cell development	1
positive regulation of programmed cell death	1
negative regulation of programmed cell death	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
positive regulation of signal transduction	1
regulation of apoptotic signaling pathway	1
regulation of programmed cell death	1
gene expression	1
endopeptidase activity	1
cysteine-type peptidase activity	1

Protein interactions and networks

STRING

1704 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP2	CRADD	P78560	999
CASP2	PIDD1	Q9HB75	998
CASP2	CYCS	P00001	841
CASP2	APAF1	O14727	812
CASP2	TRADD	Q15628	792
CASP2	TNFRSF1A	P19438	783
CASP2	NLRP1	Q9C000	760
CASP2	TP53	P04637	759
CASP2	FADD	Q13158	758
CASP2	DIABLO	Q9NR28	706
CASP2	MZB1	Q8WU39	699
CASP2	NLRP3	Q96P20	694
CASP2	BCL2	P10415	687
CASP2	NEDD1	Q8NHV4	669
CASP2	ITGB3BP	Q13352	662

IntAct

75 interactions, top by confidence:

A	B	Type	Score
CASP2	CRADD	psi-mi:“MI:0915”(physical association)	0.970
CRADD	CASP2	psi-mi:“MI:0915”(physical association)	0.970
CASP2	CRADD	psi-mi:“MI:2364”(proximity)	0.970
CRADD	CASP2	psi-mi:“MI:2364”(proximity)	0.970
CASP2	CRADD	psi-mi:“MI:0914”(association)	0.970
CRADD	CASP2	psi-mi:“MI:0914”(association)	0.970
CASP2	CASP2	psi-mi:“MI:0915”(physical association)	0.870

BioGRID (91): CASP2 (Two-hybrid), CRADD (Two-hybrid), CASP2 (Affinity Capture-MS), CASP2 (Affinity Capture-MS), CASP2 (Affinity Capture-MS), CASP2 (Affinity Capture-MS), CASP2 (Affinity Capture-MS), CASP2 (Two-hybrid), CASP2 (Two-hybrid), CASP2 (Two-hybrid), CRADD (Affinity Capture-Western), PIDD1 (Affinity Capture-Western), CASP2 (PCA), CRADD (Affinity Capture-MS), TRAF1 (Affinity Capture-MS)

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, G5EBM1, G5ECW5, O01382, O02002, O08738, O15519, O35397, O89094, O89110, P31944, P42573, P42574, P42575, P45436, P55210, P55211, P55212, P55213, P55214, P55866, P70677, P89116, P97864, Q08DY9, Q14790, Q29IM7, Q2PFV2, Q3T0P5, Q5IS54, Q5IS99, Q5RD56, Q60431, Q8C3Q9, Q8MJC3, Q8MJU1, Q8MKI5, Q92851, Q95ND5

SIGNOR signaling

11 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

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	47
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2499469	NM_032982.4(CASP2):c.1156del (p.Tyr386fs)	Pathogenic
2499470	NM_032982.4(CASP2):c.1174C>T (p.Gln392Ter)	Pathogenic
2499471	NM_032982.4(CASP2):c.130C>T (p.Arg44Ter)	Pathogenic
2499511	NM_032982.4(CASP2):c.876+1G>T	Pathogenic
985938	NM_032982.4(CASP2):c.560_561del (p.His187fs)	Likely pathogenic

SpliceAI

1515 predictions. Top by Δscore:

Variant	Effect	Δscore
7:143291536:GTA:G	acceptor_loss	1.0000
7:143291537:TAG:T	acceptor_loss	1.0000
7:143291538:A:AG	acceptor_gain	1.0000
7:143291538:A:G	acceptor_loss	1.0000
7:143291538:AG:A	acceptor_gain	1.0000
7:143291539:G:GC	acceptor_gain	1.0000
7:143291539:GG:G	acceptor_gain	1.0000
7:143291539:GGA:G	acceptor_gain	1.0000
7:143291539:GGAT:G	acceptor_gain	1.0000
7:143291539:GGATA:G	acceptor_gain	1.0000
7:143291678:G:GT	donor_gain	1.0000
7:143291688:CAGG:C	donor_loss	1.0000
7:143291689:AGG:A	donor_loss	1.0000
7:143291690:GGTAT:G	donor_loss	1.0000
7:143291691:G:T	donor_loss	1.0000
7:143291692:T:G	donor_loss	1.0000
7:143292295:CTTA:C	acceptor_loss	1.0000
7:143292296:TTAG:T	acceptor_loss	1.0000
7:143292298:A:AG	acceptor_gain	1.0000
7:143292299:G:GA	acceptor_gain	1.0000
7:143292299:G:GC	acceptor_loss	1.0000
7:143292299:GGCC:G	acceptor_gain	1.0000
7:143292299:GGCCA:G	acceptor_gain	1.0000
7:143292417:GAGGA:G	donor_gain	1.0000
7:143292420:GA:G	donor_gain	1.0000
7:143292421:A:G	donor_gain	1.0000
7:143292452:GCAT:G	donor_gain	1.0000
7:143292465:CCGG:C	donor_loss	1.0000
7:143292466:CGGT:C	donor_loss	1.0000
7:143292468:G:GG	donor_gain	1.0000

AlphaMissense

2983 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:143304689:G:C	R378P	0.998
7:143304704:G:A	G383D	0.998
7:143304709:T:A	W385R	0.998
7:143304709:T:C	W385R	0.998
7:143304704:G:T	G383V	0.997
7:143305002:G:C	K430N	0.997
7:143305002:G:T	K430N	0.997
7:143305010:C:T	S433F	0.997
7:143294681:C:A	R219S	0.996
7:143300006:T:A	H277Q	0.996
7:143300006:T:G	H277Q	0.996
7:143300266:A:C	K313N	0.996
7:143300266:A:T	K313N	0.996
7:143303904:A:T	D363V	0.996
7:143303910:T:A	I365K	0.996
7:143304683:C:A	A376D	0.996
7:143304703:G:C	G383R	0.996
7:143305021:A:C	S437R	0.996
7:143305023:C:A	S437R	0.996
7:143305023:C:G	S437R	0.996
7:143292337:T:C	L88P	0.995
7:143294654:T:C	F210L	0.995
7:143294656:C:A	F210L	0.995
7:143294656:C:G	F210L	0.995
7:143300001:T:C	S276P	0.995
7:143300002:C:G	S276W	0.995
7:143300008:G:A	G278D	0.995
7:143300271:T:C	F315S	0.995
7:143300289:G:C	R321P	0.995
7:143303916:G:A	G367D	0.995

dbSNP variants (sampled 300 via entrez): RS1000020690 (7:143299149 C>A,G), RS1000560949 (7:143290424 A>C), RS1000856564 (7:143287015 A>C), RS1001065771 (7:143303444 A>C), RS1001150486 (7:143299535 A>C,G), RS1001162035 (7:143290573 A>G), RS1001265611 (7:143306146 T>G), RS1001357034 (7:143293664 C>T), RS1001373128 (7:143292942 C>T), RS1001870461 (7:143293381 G>T), RS1002046215 (7:143304322 T>C), RS1002112710 (7:143305761 A>G), RS1002289718 (7:143287723 A>G), RS1002333891 (7:143304503 T>C,G), RS1002636413 (7:143305665 G>T)

Disease associations

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

GenCC curated gene-disease

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

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

Orphanet (0):

HPO phenotypes

25 total (25 of 25 shown, 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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

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

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

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)

23 measured of 29 human assays (29 total across all organisms); most potent 23 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-{[(4-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}phenyl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	160 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
N-(1,3,4-Trioxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-succinamic acid	IC50	859 nM
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]pyridin-2-ylmethyl}sulfamoyl)-2-hydroxy-benzoic Acid	KI	1500 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
Heterocyclic deriv. 69b	KI	2700 nM
Thiophene Scaffold 66b	KI	3200 nM
Pyridine Scaffold 4	KI	3900 nM
N-(1,2,3,4-Tetrahydro-1,3,4-trioxoisoquinolin-7-yl)-4-nitrobenzamide	IC50	5670 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
1-benzyl-5-nitro-2,3-dihydro-1H-indole-2,3-dione	KI	18000 nM
5-{[(2S)-2-[(phenylamino)methyl]pyrrolidine-1-]sulfonyl}-2,3-dihydro-1H-indole-2,3-dione	KI	21000 nM
5-{[(5-{[(2S)-1-carboxy-4-{[(2-chlorophenyl)methyl]sulfanyl}-3-oxobutan-2-yl]carbamoyl}pyrimidin-2-yl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	25000 nM
CHEMBL409053	EC50	25000 nM
CHEMBL411858	EC50	25000 nM
1,2,3,4-tetrahydroisoquinoline-1,3,4-trione	IC50	50000 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 225 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 reaction, increases expression, increases activity, increases cleavage, affects folding (+3 more)	6
benzoylcarbonyl-valyl-aspartyl-valyl-alanyl-aspartyl-fluoromethyl ketone	increases reaction, decreases activity, decreases response to substance, decreases reaction, increases activity (+1 more)	5
Doxorubicin	increases activity, increases response to substance, affects reaction, increases expression, increases splicing (+3 more)	4
bisphenol A	increases expression, affects cotreatment, affects expression, decreases expression	3
sodium arsenite	decreases expression, increases cleavage	3
1-(2-chlorobenzyl)-5’-phenyl-3’H-spiro(indoline-3,2’-(1,3,4)thiadiazol)-2-one	increases activity, affects reaction	3
Bortezomib	decreases reaction, increases activity, increases cleavage, increases reaction, affects reaction (+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	decreases reaction, increases activity, increases cleavage, increases 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 expression, increases reaction, increases cleavage	2
Diclofenac	affects expression, decreases reaction, increases activity	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	affects cotreatment, increases expression	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	increases activity, affects cotreatment	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)

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