CASP3

Summary

CASP3 (caspase 3, HGNC:1504) is a protein-coding gene on chromosome 4q35.1, encoding Caspase-3 (P42574). Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis.

The protein encoded by this gene is a cysteine-aspartic acid protease that plays a central role in the execution-phase of cell apoptosis. The encoded protein cleaves and inactivates poly(ADP-ribose) polymerase while it cleaves and activates sterol regulatory element binding proteins as well as caspases 6, 7, and 9. This protein itself is processed by caspases 8, 9, and 10. It is the predominant caspase involved in the cleavage of amyloid-beta 4A precursor protein, which is associated with neuronal death in Alzheimer’s disease.

Source: NCBI Gene 836 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 27 total — 1 pathogenic
• Druggable target: yes — 5 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_004346

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1504
Approved symbol	CASP3
Name	caspase 3
Location	4q35.1
Locus type	gene with protein product
Status	Approved
Aliases	CPP32, CPP32B, Yama, apopain
Ensembl gene	ENSG00000164305
Ensembl biotype	protein_coding
OMIM	600636
Entrez	836

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 29 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000308394, ENST00000393585, ENST00000393588, ENST00000447121, ENST00000517513, ENST00000523916, ENST00000700100, ENST00000700101, ENST00000700102, ENST00000700103, ENST00000700104, ENST00000872339, ENST00000872340, ENST00000872341, ENST00000872342, ENST00000872343, ENST00000872344, ENST00000872345, ENST00000872346, ENST00000872347, ENST00000939939, ENST00000939940, ENST00000939941, ENST00000939942, ENST00000939943, ENST00000939944, ENST00000939945, ENST00000939946, ENST00000972040, ENST00000972041, ENST00000972042, ENST00000972043

RefSeq mRNA: 9 — MANE Select: NM_004346 NM_001354777, NM_001354779, NM_001354780, NM_001354781, NM_001354782, NM_001354783, NM_001354784, NM_004346, NM_032991

CCDS: CCDS3836, CCDS87283

Canonical transcript exons

ENST00000308394 — 8 exons

Exon	Start	End
ENSE00001083265	184635294	184635418
ENSE00001083266	184632268	184632396
ENSE00001083268	184631037	184631157
ENSE00001083271	184631765	184631940
ENSE00001215704	184648465	184648631
ENSE00001592717	184649395	184649447
ENSE00002443273	184638401	184638468
ENSE00003514002	184627696	184629501

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 95.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.2886 / max 1058.2623, expressed in 1808 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55151	43.2886	1808

Top tissues by expression

277 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	95.17	gold quality
rectum	UBERON:0001052	93.30	gold quality
epithelium of nasopharynx	UBERON:0001951	92.51	silver quality
nasopharynx	UBERON:0001728	92.49	silver quality
ventricular zone	UBERON:0003053	92.23	gold quality
duodenum	UBERON:0002114	92.09	gold quality
palpebral conjunctiva	UBERON:0001812	91.76	gold quality
monocyte	CL:0000576	91.46	gold quality
esophagus squamous epithelium	UBERON:0006920	91.43	gold quality
mononuclear cell	CL:0000842	91.17	gold quality
leukocyte	CL:0000738	91.03	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.54	gold quality
ganglionic eminence	UBERON:0004023	90.41	gold quality
colonic mucosa	UBERON:0000317	90.31	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.22	gold quality
mucosa of sigmoid colon	UBERON:0004993	90.17	gold quality
vermiform appendix	UBERON:0001154	90.00	gold quality
mucosa of transverse colon	UBERON:0004991	90.00	gold quality
cortical plate	UBERON:0005343	89.48	gold quality
lymph node	UBERON:0000029	89.31	gold quality
gall bladder	UBERON:0002110	89.00	gold quality
esophagus mucosa	UBERON:0002469	88.93	gold quality
adrenal tissue	UBERON:0018303	88.87	gold quality
eye	UBERON:0000970	88.67	gold quality
oral cavity	UBERON:0000167	88.41	gold quality
nasal cavity mucosa	UBERON:0001826	88.00	gold quality
secondary oocyte	CL:0000655	87.94	gold quality
calcaneal tendon	UBERON:0003701	87.94	gold quality
nasal cavity epithelium	UBERON:0005384	87.86	silver quality
transverse colon	UBERON:0001157	87.71	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	1734.58
E-MTAB-11121	yes	1081.99
E-CURD-46	yes	18.11
E-CURD-88	no	3.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ANXA3, AR, ATF2, CEBPD, CTNNB1, DDIT3, DEAF1, DLL4, E2F1, EHF, ENO1, ETS1, EWSR1, FLI1, FOXO1, FOXO3, FOXP3, GATA2, HIF1A, ING1, ING4, JUN, LMX1B, NFKB1, NKX3-1, NOTCH1, PARP1, PHF10, PML, POU1F1, PPARA, PROP1, RBM10, RBPJ, RELA, ROCK1, RUNX3, SIM2, SLC22A2, SMAD5

miRNA regulators (miRDB)

98 targeting CASP3, 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-4795-3P	100.00	74.62	4024
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-7-1-3P	99.91	71.53	4384

Literature-anchored findings (GeneRIF, showing 40)

• A soluble proform of caspase 3 containing a fortuitous mutation (W206R) is inactive when incubated with recombinant human caspase 8 and therefore can serve as a useful reagent to test the efficacy of caspase 8 inhibitors. (PMID:11437602)
• Enzyme activation of caspase-3 was observed in apoptosis of K562 human cell line. (PMID:11787859)
• caspase-3 may participate in the regulation mechanism of lymphoma cel apoptosis. (PMID:11866986)
• Activation of caspase-3 and cleavage of Rb are associated with p16-mediated apoptosis in human non-small cell lung cancer cells. (PMID:11960384)
• caspase 3-mediated focal adhesion kinase processing in human ovarian cancer cells: possible regulation by X-linked inhibitor of apoptosis protein (PMID:11972398)
• investigation of molecular mechanism of MPO-mediated apoptosis and caspase-3 activation (PMID:11981455)
• These data suggest that D4-GDI of Rho family GTPase may be regulated during apoptosis through the caspase-3 mediated cleavage of the GDI protein. (PMID:11989976)
• Clinical significance of caspase-3 expression in pathologic-stage I, nonsmall-cell lung cancer (PMID:11992386)
• translation of some IRES-containing mRNAs is regulated by proteolytic cleavage of PTB during apoptosis (PMID:12004072)
• results suggest that IGF-1/PI-3 kinase inhibited C2-ceramide-induced apoptosis due to relieving oxidative damage, which resulted from the inhibition of catalase by activated caspase-3 (PMID:12032677)
• Expression levels of apoptosis-related proteins caspase 3, Bcl-2, and PI9 predict clinical outcome in anaplastic large cell lymphoma. (PMID:12036886)
• Identification of high caspase-3 mRNA expression as a unique signature profile for extremely old individuals (PMID:12044963)
• The significant expression of caspase-3 that occurs in monocytes during serum-deprived induction of apoptosis can be down-regulated to baseline levels by addition of platelets. (PMID:12055227)
• High numbers of active caspase 3-positive Reed-Sternberg cells in pretreatment biopsy specimens of patients with Hodgkin disease predict favorable clinical outcome. (PMID:12070005)
• Caspase-cleaved amyloid precursor protein and activated caspase-3 are co-localized in the granules of granulovacuolar degeneration in Alzheimer’s disease and Down’s syndrome brain. (PMID:12070657)
• Selective inhibition of dipeptidyl peptidase I, not caspases, prevents the partial processing of procaspase-3 in CD3-activated human CD8(+) T lymphocytes (PMID:12080079)
• Pro-CASP3 moved to the the mitochondria of U937 cells during TPA-induced differentiation. (PMID:12145703)
• caspase 3 cleaves CDC6 during apoptosis, which prevents wounded cell from replicating and facilitates death (PMID:12151338)
• Both oleandrin and radiation share a caspase-3 dependent mechanism of apoptosis in the PC-3 human prostate cacncer cell line. (PMID:12169388)
• Hypoxia-induced cleavage of caspase-3 and DFF45/ICAD in human failed cardiomyocytes. (PMID:12181128)
• Role of nuclear PKC delta in mediating caspase-3-upregulation in Jurkat T leukemic cells exposed to ionizing radiation (PMID:12210761)
• Data show that endoplasmic reticulum stress induced by thapsigargin not only activated the apoptosis effector caspase-3 but also caused a large and prolonged increase in the activity of glycogen synthase kinase-3beta. (PMID:12228224)
• caspase 3-independent function of Bak in the TNF-alpha-induced apoptotic pathway (PMID:12297281)
• The apoptosis resistance of mdr cells is not related to the abnormality of CPP32 but the upstream of caspase, the fact of which indicates promising prospect of the research on reversion of mdr cells using CPP32 as target. (PMID:12390838)
• caspase 3 activation and apoptosis are blocked by LIGHT protein in hepatocytes (PMID:12393901)
• A significant positive correlation between in-situ active caspase-3 in the sperm midpiece and DNA fragmentation was observed in the low motility fractions of patients. (PMID:12397210)
• IFN-gamma-mediated caspase-3 activation and C. burnetii killing depend on the expression of membrane TNF. (PMID:12444137)
• determination of levels of caspase-3 expression in breast tumor samples and to determine whether alterations in its expression can affect their ability to undergo apoptosis (PMID:12483536)
• ceramide increases oxidative damage by inhibition of ROS scavenging ability through caspase-3-dependent proteolysis of catalase (PMID:12511568)
• caspase 3 has a role in damaging mitochondrial function and generating reactive oxygen species after activation by cytochrome c (PMID:12515825)
• Presentation of nitric oxide regulates monocyte survival through effects on this enzyme and caspase-9 activation. (PMID:12566444)
• induction of ceramide accumulation by various triggers of ceramide generation triggered the activation of caspase-3. (PMID:12576296)
• mRNA and protein expression of this enzyme are examined in breast cancer to determine level of apoptosis. (PMID:12576443)
• CASP3 induced by H202 was completely blocked by Z-VAD-fmk. (PMID:12579342)
• caspase-3 is essential for efficient induction of apoptosis by staurosporine, but not for mitochondrial steps that occur earlier in the pathway (PMID:12581734)
• one or more distinct cellular mechanisms regulate Bid cleavage by caspases 8 and 3 in situ. (PMID:12598529)
• caspase-3 was upregulated in a region-specific manner with marked activation in the selectively vulnerable hippocampal after cerebral ischemia (PMID:12605885)
• Data report that human oocytes and fragmenting preimplantation embryos possess transcripts encoding Harakiri and caspase-3. (PMID:12606589)
• caspase-3-mediated proteolysis of FAK, an anti-apoptotic protein, is regulated by hsp72 (PMID:12611892)
• in neutrophils, functional expression of caspase-3 in neutrophils may be regulated during ontogeny. (PMID:12621124)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp3a	ENSDARG00000017905
danio_rerio	casp3b	ENSDARG00000055045
mus_musculus	Casp3	ENSMUSG00000031628
rattus_norvegicus	Casp3	ENSRNOG00000010475
drosophila_melanogaster	Dcp-1	FBGN0010501
drosophila_melanogaster	Drice	FBGN0019972
caenorhabditis_elegans		WBGENE00000417
caenorhabditis_elegans		WBGENE00000820
caenorhabditis_elegans	csp-3	WBGENE00000821

Paralogs (16): CASP10 (ENSG00000003400), CFLAR (ENSG00000003402), CASP8 (ENSG00000064012), PYCARD (ENSG00000103490), CASP14 (ENSG00000105141), CASP2 (ENSG00000106144), CASP9 (ENSG00000132906), CASP1 (ENSG00000137752), CASP5 (ENSG00000137757), CASP6 (ENSG00000138794), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CASP4 (ENSG00000196954), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Protein

Protein identifiers

Caspase-3 — P42574 (reviewed: P42574)

Alternative names: Apopain, Cysteine protease CPP32, Protein Yama, SREBP cleavage activity 1

All UniProt accessions (4): A0A8V8TPU5, A8MVM1, C9JXR7, P42574

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease that acts as a major effector caspase involved in the execution phase of apoptosis. Following cleavage and activation by initiator caspases (CASP8, CASP9 and/or CASP10), mediates execution of apoptosis by catalyzing cleavage of many proteins. At the onset of apoptosis, it proteolytically cleaves poly(ADP-ribose) polymerase PARP1 at a ‘216-Asp-|-Gly-217’ bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9 (CASP6, CASP7 and CASP9, respectively). Cleaves and inactivates interleukin-18 (IL18). Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage. Cleaves DSG2 in response to apoptosis resulting in a loss of full length DSG2 at desmosome cell junctions and subsequent loss of cell-cell adhesion. Also cleaves JUP in response to apoptosis. Cleaves and inhibits serine/threonine-protein kinase AKT1 in response to oxidative stress. Acts as an inhibitor of type I interferon production during virus-induced apoptosis by mediating cleavage of antiviral proteins CGAS, IRF3 and MAVS, thereby preventing cytokine overproduction. Also involved in pyroptosis by mediating cleavage and activation of gasdermin-E (GSDME). Cleaves XRCC4 and phospholipid scramblase proteins XKR4, XKR8 and XKR9, leading to promote phosphatidylserine exposure on apoptotic cell surface. Cleaves BIRC6 following inhibition of BIRC6-caspase binding by DIABLO/SMAC.

Subunit / interactions. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 17 kDa (p17) and a 12 kDa (p12) subunit. Interacts with BIRC6/bruce.

Subcellular location. Cytoplasm.

Tissue specificity. Highly expressed in lung, spleen, heart, liver and kidney. Moderate levels in brain and skeletal muscle, and low in testis. Also found in many cell lines, highest expression in cells of the immune system.

Post-translational modifications. Cleavage by granzyme B, caspase-6, caspase-8 and caspase-10 generates the two active subunits. Additional processing of the propeptides is likely due to the autocatalytic activity of the activated protease. Active heterodimers between the small subunit of caspase-7 protease and the large subunit of caspase-3 also occur and vice versa. S-nitrosylated on its catalytic site cysteine in unstimulated human cell lines and denitrosylated upon activation of the Fas apoptotic pathway, associated with an increase in intracellular caspase activity. Fas therefore activates caspase-3 not only by inducing the cleavage of the caspase zymogen to its active subunits, but also by stimulating the denitrosylation of its active site thiol. Ubiquitinated by BIRC6; this activity is inhibited by DIABLO/SMAC. (Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP3 processing, preventing CASP3 activation and ability to recognize and cleave substrates.

Activity regulation. Inhibited by isatin sulfonamides. Inhibited by BIRC6; following inhibition of BIRC6-caspase binding by DIABLO/SMAC, BIRC6 is subjected to caspase cleavage, leading to an increase in active caspases.

Similarity. Belongs to the peptidase C14A family.

RefSeq proteins (9): NP_001341706, NP_001341708, NP_001341709, NP_001341710, NP_001341711, NP_001341712, NP_001341713, NP_004337, NP_116786 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001309	Pept_C14_p20	Domain
IPR002138	Pept_C14_p10	Domain
IPR002398	Pept_C14	Family
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

Pfam: PF00656

Enzyme classification (BRENDA):

• EC 3.4.22.56 — caspase-3 (BRENDA: 15 organisms, 215 substrates, 504 inhibitors, 53 Km, 35 kcat entries)

Substrate kinetics (BRENDA)

33 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-DEVD-7-AMIDO-4-METHYLCOUMARIN	0.005–10.7	10
ACETYL-L-ASP-L-GLU-L-VAL-L-ASP-7-AMIDO-4-METHYLC	0.0048–0.0335	6
BENZOYL-L-ASP-L-GLU-L-VAL-L-ASP-7-AMIDO-4-METHYL	0.002–0.0255	6
5’-TETRAMETHYLRHODAMINE-5(6)-CARBOXAMIDE-DEVD-CY	0.0016	1
AC-DEVD-4-METHYLCOUMARIN 7-AMIDE	0.0337	1
ACETYL-DEVD-4-NITROANILIDE	0.011	1
ACETYL-DQMD-4-NITROANILIDE	0.044	1
ACETYL-L-ASP-L-GLU-L-VAL-L-ASP-4-NITROANILIDE	0.067	1
ACETYL-L-ASP-L-MET-L-GLN-L-ASP-4-NITROANILIDE	1.6	1
ACETYL-L-ASP-L-VAL-L-ALA-L-ASP-4-NITROANILIDE	0.222	1
ACETYL-L-LEU-L-ASP-L-VAL-L-ALA-L-ASP-4-NITROANIL	0.147	1
ACETYL-L-VAL-L-ASP-L-VAL-L-ALA-L-ASP-4-NITROANIL	0.164	1
ACETYL-VDQMDGW-AMIDE	0.2	1
ACETYL-VDVAD-4-NITROANILIDE	0.067	1
ACETYL-VEID-4-NITROANILIDE	0.25	1

UniProt features (44 total): strand 12, helix 9, modified residue 5, turn 5, mutagenesis site 4, propeptide 2, sequence variant 2, chain 2, active site 2, sequence conflict 1

Structure

Experimental structures (PDB)

135 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2DKO	X-RAY DIFFRACTION	1.06
2J32	X-RAY DIFFRACTION	1.3
5IBP	X-RAY DIFFRACTION	1.38
2J30	X-RAY DIFFRACTION	1.4
4JJE	X-RAY DIFFRACTION	1.48
4QUJ	X-RAY DIFFRACTION	1.5
2J31	X-RAY DIFFRACTION	1.5
3PCX	X-RAY DIFFRACTION	1.5
6CKZ	X-RAY DIFFRACTION	1.5
6CL0	X-RAY DIFFRACTION	1.5
6X8I	X-RAY DIFFRACTION	1.5
2XYG	X-RAY DIFFRACTION	1.54
5IAS	X-RAY DIFFRACTION	1.54
6BFO	X-RAY DIFFRACTION	1.54
6BFJ	X-RAY DIFFRACTION	1.54
5IAE	X-RAY DIFFRACTION	1.55
4QU9	X-RAY DIFFRACTION	1.56
5IAJ	X-RAY DIFFRACTION	1.58
4EHD	X-RAY DIFFRACTION	1.58
1NME	X-RAY DIFFRACTION	1.6
6BGS	X-RAY DIFFRACTION	1.6
4QTY	X-RAY DIFFRACTION	1.6
6BHA	X-RAY DIFFRACTION	1.6
3EDQ	X-RAY DIFFRACTION	1.61
3PD1	X-RAY DIFFRACTION	1.62
3ITN	X-RAY DIFFRACTION	1.63
4PS0	X-RAY DIFFRACTION	1.63
4EHF	X-RAY DIFFRACTION	1.66
5IBC	X-RAY DIFFRACTION	1.66
4EHK	X-RAY DIFFRACTION	1.67

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P42574-F1	86.64	0.77

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): 121; 163

Post-translational modifications (5): 207, 1, 11, 26, 163

Mutagenesis-validated functional residues (4):

Position	Phenotype
9	in p3-d3a mutant; abolished cleavage and activation, leading to prevent thiol protease activity; when associated with a-
28	in p3-d3a mutant; abolished cleavage and activation, leading to prevent thiol protease activity; when associated with a-
175	in p3-d3a mutant; abolished cleavage and activation, leading to prevent thiol protease activity; when associated with a-
207	abolished adp-riboxanation by c.violaceum copc.

Function

Pathways and Gene Ontology

Reactome pathways

33 pathways

ID	Pathway
R-HSA-111459	Activation of caspases through apoptosome-mediated cleavage
R-HSA-111463	SMAC (DIABLO) binds to IAPs
R-HSA-111464	SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes
R-HSA-111465	Apoptotic cleavage of cellular proteins
R-HSA-111469	SMAC, XIAP-regulated apoptotic response
R-HSA-140342	Apoptosis induced DNA fragmentation
R-HSA-1474228	Degradation of the extracellular matrix
R-HSA-2028269	Signaling by Hippo
R-HSA-205025	NADE modulates death signalling
R-HSA-211736	Stimulation of the cell death response by PAK-2p34
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins
R-HSA-351906	Apoptotic cleavage of cell adhesion proteins
R-HSA-418889	Caspase activation via Dependence Receptors in the absence of ligand
R-HSA-449836	Other interleukin signaling
R-HSA-5620971	Pyroptosis
R-HSA-9960519	CASP4-mediated substrate cleavage
R-HSA-9960525	CASP5-mediated substrate cleavage
R-HSA-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-111461	Cytochrome c-mediated apoptotic response
R-HSA-111471	Apoptotic factor-mediated response
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1474244	Extracellular matrix organization
R-HSA-162582	Signal Transduction
R-HSA-168256	Immune System
R-HSA-193704	p75 NTR receptor-mediated signalling
R-HSA-204998	Cell death signalling via NRAGE, NRIF and NADE
R-HSA-449147	Signaling by Interleukins
R-HSA-5218859	Regulated Necrosis
R-HSA-5357769	Caspase activation via extrinsic apoptotic signalling pathway

MSigDB gene sets: 668 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, REACTOME_APOPTOSIS_INDUCED_DNA_FRAGMENTATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_RESPONSE_TO_ETHANOL, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_IONIZING_RADIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_NEURON_RECOGNITION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_COGNITION, GOBP_B_CELL_HOMEOSTASIS

GO Biological Process (67): luteolysis (GO:0001554), response to hypoxia (GO:0001666), B cell homeostasis (GO:0001782), negative regulation of cytokine production (GO:0001818), proteolysis (GO:0006508), apoptotic process (GO:0006915), DNA damage response (GO:0006974), axonal fasciculation (GO:0007413), heart development (GO:0007507), sensory perception of sound (GO:0007605), learning or memory (GO:0007611), intrinsic apoptotic signaling pathway in response to osmotic stress (GO:0008627), response to xenobiotic stimulus (GO:0009410), response to UV (GO:0009411), response to wounding (GO:0009611), response to glucose (GO:0009749), response to X-ray (GO:0010165), regulation of macroautophagy (GO:0016241), protein processing (GO:0016485), hippocampus development (GO:0021766), protein catabolic process (GO:0030163), neuron differentiation (GO:0030182), keratinocyte differentiation (GO:0030216), erythrocyte differentiation (GO:0030218), platelet formation (GO:0030220), negative regulation of B cell proliferation (GO:0030889), regulation of protein stability (GO:0031647), response to cobalt ion (GO:0032025), response to estradiol (GO:0032355), response to lipopolysaccharide (GO:0032496), glial cell apoptotic process (GO:0034349), response to tumor necrosis factor (GO:0034612), response to nicotine (GO:0035094), swimming behavior (GO:0036269), response to hydrogen peroxide (GO:0042542), T cell homeostasis (GO:0043029), response to amino acid (GO:0043200), positive regulation of neuron apoptotic process (GO:0043525), fibroblast apoptotic process (GO:0044346), cell fate commitment (GO:0045165)

GO Molecular Function (13): protease binding (GO:0002020), aspartic-type endopeptidase activity (GO:0004190), cysteine-type endopeptidase activity (GO:0004197), cyclin-dependent protein serine/threonine kinase inhibitor activity (GO:0004861), death receptor binding (GO:0005123), enzyme activator activity (GO:0008047), peptidase activity (GO:0008233), phospholipase A2 activator activity (GO:0016005), protein-containing complex binding (GO:0044877), endopeptidase activity (GO:0004175), protein binding (GO:0005515), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), postsynaptic density (GO:0014069), death-inducing signaling complex (GO:0031264), neuronal cell body (GO:0043025), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Apoptotic execution phase	3
SMAC, XIAP-regulated apoptotic response	2
Apoptotic factor-mediated response	2
Apoptotic cleavage of cellular proteins	2
Non-canonical inflammasome activation	2
Cytochrome c-mediated apoptotic response	1
Extracellular matrix organization	1
Signal Transduction	1
Cell death signalling via NRAGE, NRIF and NADE	1
Caspase activation via extrinsic apoptotic signalling pathway	1
Signaling by Interleukins	1
Regulated Necrosis	1
Programmed Cell Death	1
Apoptosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to stress	2
endopeptidase activity	2
catalytic activity	2
binding	2
peptidase activity	2
female gonad development	1
ovulation cycle process	1
response to decreased oxygen levels	1
lymphocyte homeostasis	1
cytokine production	1
regulation of cytokine production	1
negative regulation of gene expression	1
negative regulation of multicellular organismal process	1
protein metabolic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
neuron recognition	1
axon development	1
neuron projection fasciculation	1
animal organ development	1
circulatory system development	1
sensory perception of mechanical stimulus	1
behavior	1
cognition	1
cellular response to osmotic stress	1
intrinsic apoptotic signaling pathway	1
response to chemical	1
response to light stimulus	1
response to hexose	1
response to ionizing radiation	1
regulation of autophagy	1
macroautophagy	1
proteolysis	1
protein maturation	1
pallium development	1
limbic system development	1
anatomical structure development	1

Protein interactions and networks

STRING

8154 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP3	XIAP	P98170	998
CASP3	APAF1	O14727	986
CASP3	CASP8	Q14790	984
CASP3	BCL2	P10415	980
CASP3	CYCS	P00001	975
CASP3	CASP9	P55211	958
CASP3	PARP1	P09874	954
CASP3	BCL2L1	Q07817	940
CASP3	TP53	P04637	937
CASP3	TNF	P01375	932
CASP3	AKT1	P31749	923
CASP3	MAPK8	P45983	923
CASP3	BIRC3	Q13489	922
CASP3	FADD	Q13158	920
CASP3	ANXA5	P08758	919

IntAct

143 interactions, top by confidence:

A	B	Type	Score
XIAP	CASP3	psi-mi:“MI:0915”(physical association)	0.870
CASP3	XIAP	psi-mi:“MI:0914”(association)	0.870
CASP3	XIAP	psi-mi:“MI:0915”(physical association)	0.870
CASP3	XIAP	psi-mi:“MI:2364”(proximity)	0.870
XIAP	CASP3	psi-mi:“MI:0407”(direct interaction)	0.870
TXN	CASP3	psi-mi:“MI:0915”(physical association)	0.750
TXN	CASP3	psi-mi:“MI:0407”(direct interaction)	0.750
TXN	CASP3	psi-mi:“MI:0570”(protein cleavage)	0.750
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
APP	CASP3	psi-mi:“MI:0915”(physical association)	0.660
CASP3	APP	psi-mi:“MI:2364”(proximity)	0.660
APAF1	CASP3	psi-mi:“MI:0194”(cleavage reaction)	0.650
APAF1	CASP3	psi-mi:“MI:0407”(direct interaction)	0.650
CASP3	APAF1	psi-mi:“MI:0194”(cleavage reaction)	0.650
CASP3	CASP9	psi-mi:“MI:0194”(cleavage reaction)	0.640
MED20	MED14	psi-mi:“MI:0914”(association)	0.640
CASP9	CASP3	psi-mi:“MI:2364”(proximity)	0.640
CASP9	CASP3	psi-mi:“MI:0914”(association)	0.640

BioGRID (235): PARP1 (Biochemical Activity), PTGES3 (Biochemical Activity), CASP3 (Co-fractionation), BECN1 (Biochemical Activity), PARP1 (Biochemical Activity), ATG4D (Biochemical Activity), PARP1 (Biochemical Activity), XIAP (Affinity Capture-MS), C6orf211 (Co-fractionation), CASP3 (Co-fractionation), CASP3 (Co-fractionation), EEF2 (Co-fractionation), LCMT1 (Co-fractionation), SERPINB8 (Co-fractionation), CASP3 (Synthetic Growth Defect)

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

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

SIGNOR signaling

76 interactions.

A	Effect	B	Mechanism
CASP3	“down-regulates activity”	PTCH1	cleavage
CASP3	up-regulates	ROCK1	cleavage
XIAP	“down-regulates quantity by destabilization”	CASP3	ubiquitination
XIAP	“down-regulates activity”	CASP3	binding
CASP3	down-regulates	IKBKB	cleavage
MAPK14	down-regulates	CASP3	phosphorylation
BIRC6	down-regulates	CASP3	binding
CASP3	“up-regulates activity”	BAD	cleavage
PPP2R5B	up-regulates	CASP3	dephosphorylation
CASP3	“up-regulates activity”	CASP9	cleavage
CASP9	“up-regulates activity”	CASP3	cleavage
CASP8	“up-regulates activity”	CASP3	cleavage
CASP3	down-regulates	PSIP1	cleavage
PAC-1	up-regulates	CASP3	“chemical activation”
CASP3	down-regulates	PTCH1	cleavage
ING1	“up-regulates quantity by expression”	CASP3	“transcriptional regulation”
CASP3	“down-regulates quantity by destabilization”	BRCA1	cleavage
CASP3	“down-regulates activity”	GSN	cleavage
“Caspase 9 complex”	“up-regulates activity”	CASP3	cleavage
“Caspase 8 complex”	“up-regulates activity”	CASP3	cleavage
Apoptosome	“up-regulates activity”	CASP3	cleavage
CASP3	up-regulates	Cell_death
RBM10	“down-regulates quantity by repression”	CASP3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	62.6×	3e-08
Activation of BH3-only proteins	6	40.8×	3e-07
Constitutive Signaling by AKT1 E17K in Cancer	7	40.6×	3e-08
Intrinsic Pathway for Apoptosis	9	36.1×	4e-10
PI3K/AKT Signaling in Cancer	7	35.3×	6e-08
VEGFR2 mediated vascular permeability	6	33.5×	1e-06
Apoptotic cleavage of cellular proteins	5	32.6×	1e-05
Apoptotic execution phase	5	32.6×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
epidermal growth factor receptor signaling pathway	5	15.7×	2e-03
response to estradiol	5	12.6×	4e-03
protein autophosphorylation	6	11.0×	2e-03
cellular response to insulin stimulus	5	10.8×	7e-03
positive regulation of JNK cascade	5	10.4×	7e-03
MAPK cascade	5	9.7×	8e-03
response to ethanol	5	9.3×	8e-03
protein import into nucleus	5	9.1×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	16
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
562989	GRCh37/hg19 4q32.1-35.2(chr4:159492464-190957473)x3	Pathogenic

SpliceAI

1335 predictions. Top by Δscore:

Variant	Effect	Δscore
4:184629498:TAAC:T	acceptor_gain	1.0000
4:184631158:C:CC	acceptor_gain	1.0000
4:184631162:G:GC	acceptor_gain	1.0000
4:184631165:T:C	acceptor_gain	1.0000
4:184631165:T:TC	acceptor_gain	1.0000
4:184631759:CATTA:C	donor_loss	1.0000
4:184631760:ATTAC:A	donor_loss	1.0000
4:184631761:TTAC:T	donor_loss	1.0000
4:184631762:TAC:T	donor_loss	1.0000
4:184631763:A:C	donor_loss	1.0000
4:184631764:CCT:C	donor_loss	1.0000
4:184631936:AGAAA:A	acceptor_gain	1.0000
4:184631937:GAAA:G	acceptor_gain	1.0000
4:184631938:AAA:A	acceptor_gain	1.0000
4:184631939:AA:A	acceptor_gain	1.0000
4:184631941:C:A	acceptor_loss	1.0000
4:184631941:C:CC	acceptor_gain	1.0000
4:184631943:G:C	acceptor_gain	1.0000
4:184631943:G:GC	acceptor_gain	1.0000
4:184631950:CAT:C	acceptor_gain	1.0000
4:184631951:A:C	acceptor_gain	1.0000
4:184631951:A:T	acceptor_gain	1.0000
4:184631953:T:C	acceptor_gain	1.0000
4:184631953:T:TC	acceptor_gain	1.0000
4:184631956:CAAA:C	acceptor_gain	1.0000
4:184631959:A:AC	acceptor_gain	1.0000
4:184631959:A:C	acceptor_gain	1.0000
4:184632262:TCTTA:T	donor_loss	1.0000
4:184632263:CTTA:C	donor_loss	1.0000
4:184632264:TTACC:T	donor_loss	1.0000

AlphaMissense

1866 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:184635307:A:C	F55L	1.000
4:184635307:A:T	F55L	1.000
4:184635309:A:G	F55L	1.000
4:184629376:C:G	A244P	0.999
4:184629486:C:G	R207P	0.999
4:184631048:G:A	S198F	0.999
4:184631885:A:C	H121Q	0.999
4:184631885:A:T	H121Q	0.999
4:184631888:G:C	S120R	0.999
4:184631888:G:T	S120R	0.999
4:184631890:T:G	S120R	0.999
4:184635308:A:G	F55S	0.999
4:184635331:A:C	C47W	0.999
4:184629323:C:A	Q261H	0.998
4:184629323:C:G	Q261H	0.998
4:184629461:G:C	F215L	0.998
4:184629461:G:T	F215L	0.998
4:184629463:A:G	F215L	0.998
4:184629471:C:A	G212V	0.998
4:184629471:C:T	G212D	0.998
4:184629490:A:G	W206R	0.998
4:184629490:A:T	W206R	0.998
4:184629492:G:A	S205F	0.998
4:184631048:G:T	S198Y	0.998
4:184631078:G:T	P188Q	0.998
4:184631148:C:A	G165C	0.998
4:184631148:C:G	G165R	0.998
4:184631150:C:G	R164P	0.998
4:184631157:C:G	A162P	0.998
4:184631775:A:G	F158S	0.998

dbSNP variants (sampled 300 via entrez): RS1000212547 (4:184644874 C>A,G), RS1000254586 (4:184636386 C>T), RS1000427285 (4:184642352 A>G), RS1000493001 (4:184650206 C>G), RS1000709111 (4:184638949 CTTTTTT>C,CTT,CTTT,CTTTT,CTTTTT,CTTTTTTT,CTTTTTTTTT,CTTTTTTTTTT,CTTTTTTTTTTT), RS1000710212 (4:184637476 T>G), RS1000772556 (4:184636204 A>C,T), RS1000819376 (4:184643517 C>T), RS1001000436 (4:184637796 G>T), RS1001241267 (4:184628274 C>T), RS1001335065 (4:184631644 A>G), RS10014306 (4:184631543 A>C,T), RS1001662772 (4:184634804 T>C), RS1001673156 (4:184650774 C>A,T), RS1001753165 (4:184628505 A>G)

Disease associations

OMIM: gene MIM:600636 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006993_6	Hippocampal volume in Alzheimer’s disease dementia	2.000000e-07
GCST010979_1	Kawasaki disease	2.000000e-08
GCST90013537_7	Kawasaki disease	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005035	hippocampal volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2334 (SINGLE PROTEIN), CHEMBL3430905 (PROTEIN FAMILY), CHEMBL3831289 (PROTEIN FAMILY), CHEMBL3885517 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 15,675 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL41286	DIACEREIN	3	5,090
CHEMBL165790	IPRIFLAVONE	2	5,477
CHEMBL197672	EMRICASAN	2	1,509
CHEMBL437526	PRALNACASAN	2	1,398
CHEMBL591429	PAC-1	1	2,201

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2720376	CASP3		0.00	0
rs113420705	CASP3, PRIMPOL		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C14: Caspase

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
Ac-DEVD-CHO	Inhibition	9.8	pIC50
M826	Inhibition	8.3	pKi
compound 4 [PMID: 12408711]	Inhibition	7.3	pKi
AZ10417808	Inhibition	6.61	pKi

Binding affinities (BindingDB)

1005 measured of 1191 human assays (1222 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Ethyl 5-Amino-3-(4-methoxyphenyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-carboxylate	EC50	0.0145 nM
(S)-5-[(7-Aza-bicyclo[2.2.1]hept-7-ylmethyl)-amino]-3-(2-{3-[(4-methyl-furazan-3-ylmethyl)-amino]-2-oxo-2H-pyrazin-1-yl}-butyrylamino)-4-oxo-pentanoic acid	IC50	0.023 nM
(3S)-3-[(2S)-2-[(4S)-4-[(3S)-3-acetamido-3-formamidopropanoic acid]-4-formamidobutanoic acid]-3-methylbutanamido]-4-oxo-7-phenylheptanoic acid	IC50	0.771 nM
pyrimidoindolone, 25b	IC50	1.29 nM
pyrimidoindolone, 25d	IC50	2.32 nM
pyrimidoindolone, 11k	IC50	2.4 nM
(3S)-5-(benzylsulfanyl)-3-{[(2S,11S)-11-[(3S)-3-acetamido-3-formamidopropanoic acid]-12-oxo-1-azatricyclo[6.4.1.0^{4,13}]trideca-4(13),5,7-trien-2-yl]formamido}-4-oxopentanoic acid	IC50	3 nM
tert-butyl 2-(2,3-dioxo-5-{[(2S)-2-(phenoxymethyl)pyrrolidine-1-]sulfonyl}-2,3-dihydro-1H-indol-1-yl)acetate	IC50	3.1 nM
pyrimidoindolone, 25a	IC50	3.3 nM
7-methyl-12-(morpholine-4-sulfonyl)-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaene-3,5-dione	IC50	4 nM
(S)-1-(4-Pyridinylmethyl)-5-{1-[2-(phenoxymethyl)pyrrolidinyl]sulfonyl}isatin	IC50	4.2 nM
pyrimidoindolone, 11l	IC50	4.43 nM
(S)-1-Allyl-5-{1-[2-(phenoxymethyl)pyrrolidinyl]sulfonyl}isatin	IC50	4.6 nM
pyrimidoindolone, 14a	IC50	4.99 nM
1-(cyclohexylmethyl)-5-{[(2S)-2-(phenoxymethyl)pyrrolidine-1-]sulfonyl}-2,3-dihydro-1H-indole-2,3-dione	IC50	5.2 nM
pyrimidoindolone, 11m	IC50	7.18 nM
pyrimidoindolone, 11h	IC50	7.81 nM
Compound 6	IC50	9.17 nM
pyrimidoindolone, 11n	IC50	10.1 nM
pyrimidoindolone, 11i	IC50	10.2 nM
pyrimidoindolone, 11a	IC50	10.8 nM
(3S)-3-[[(2S)-1-acetylpyrrolidine-2-carbonyl]amino]-5-(2,6-dimethylbenzoyl)oxy-4-oxopentanoic acid	IC50	11.5 nM	US-9345789: Specific inhibitors and active site probes for legumain
pyrimidoindolone, 11j	IC50	12.6 nM
pyrimidoindolone, 25e	IC50	13.6 nM
pyrimidoindolone, 11b	IC50	13.8 nM
pyrimidoindolone, 14b	IC50	14.3 nM
pyrimidoindolone, 25c	IC50	14.8 nM
7-methyl-4-(2-methylphenyl)-12-(morpholine-4-sulfonyl)-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaene-3,5-dione	IC50	15 nM
methyl 2-[7-methyl-12-(morpholine-4-sulfonyl)-3,5-dioxo-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaen-4-yl]acetate	IC50	16 nM
7-methyl-3,5-dioxo-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaene-12-carbonitrile	IC50	16 nM
2-hydroxy-N-[7-methyl-3,5-dioxo-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaen-12-yl]ethane-1-sulfonamido	IC50	20 nM
5-{[(5-{[(2S)-1-carboxy-3-oxo-4-[(pyridin-3-ylmethyl)sulfanyl]butan-2-yl]carbamoyl}thiophen-2-yl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	20 nM
5-{[(5-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}pyrimidin-2-yl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	20 nM
CHEMBL4226512	IC50	20 nM
N-(2-methoxyethyl)-7-methyl-3,5-dioxo-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaene-12-sulfonamide	IC50	21 nM
2-[7-methyl-12-(morpholine-4-sulfonyl)-3,5-dioxo-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaen-4-yl]ethyl acetate	IC50	23 nM
methyl (2S)-2-{[7-methyl-3,5-dioxo-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaene-12-]sulfonamido}-3-phenylpropanoate	IC50	23 nM
pyrimidoindolone, 11f	IC50	23 nM
4-methoxy-N-(6-methoxy-4H-indeno[1,2-d][1,3]thiazol-2-yl)benzamide	IC50	23 nM
pyrimidoindolone, 25f	IC50	24.6 nM
2-[12-(morpholine-4-sulfonyl)-3,5-dioxo-7-phenyl-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaen-4-yl]ethyl acetate	IC50	27 nM
isatin Michael acceptor (IMA) analogue, 3	IC50	27.8 nM
(S)-5-({5-[1-Carboxymethyl-2-oxo-3-(pyridin-4-ylmeth-ylsulfanyl)propylcarbamoyl]thiophen-2-ylmethyl}-sulfamoyl)-2-hydroxy-benzoic Acid	KI	30 nM
pyrimidoindolone, 11d	IC50	30 nM
2-[12-(morpholine-4-sulfonyl)-3,5-dioxo-7-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaen-4-yl]ethyl acetate	IC50	33 nM
2-[7-(3-chloro-4-fluorophenyl)-12-(morpholine-4-sulfonyl)-3,5-dioxo-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaen-4-yl]ethyl acetate	IC50	33 nM
2-[12-(morpholine-4-sulfonyl)-3,5-dioxo-7-(pyridin-3-yl)-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaen-4-yl]ethyl acetate	IC50	33 nM
7-methyl-3,5-dioxo-4-(1,3,5-trimethyl-1H-pyrazol-4-yl)-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaene-12-sulfonamide	IC50	33 nM
2-[7-(furan-2-yl)-12-(morpholine-4-sulfonyl)-3,5-dioxo-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaen-4-yl]ethyl acetate	IC50	36 nM
methyl 3-[7-methyl-12-(morpholine-4-sulfonyl)-3,5-dioxo-4,8-diazatricyclo[7.4.0.0^{2,6}]trideca-1(13),2(6),7,9,11-pentaen-4-yl]propanoate	IC50	37 nM

ChEMBL bioactivities

1591 potent at pChembl≥5 of 2367 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.10	Ki	0.08	nM	CHEMBL4751195
10.00	IC50	0.1	nM	CHEMBL180669
9.70	IC50	0.2	nM	CHEMBL417149
9.70	Ki	0.2	nM	CHEMBL213759
9.64	Ki	0.23	nM	CHEMBL5723373
9.52	IC50	0.3	nM	CHEMBL178116
9.52	IC50	0.3	nM	CHEMBL213759
9.30	EC50	0.5	nM	CHEMBL456799
9.30	IC50	0.5	nM	CHEMBL456799
9.17	Ki	0.68	nM	CHEMBL5723360
9.11	IC50	0.771	nM	CHEMBL443565
9.10	IC50	0.8	nM	CHEMBL443565
9.10	Ki	0.8	nM	CHEMBL216071
9.00	Ki	1	nM	CHEMBL5641709
8.94	IC50	1.15	nM	CHEMBL3233630
8.92	Ki	1.2	nM	CHEMBL384023
8.92	Ki	1.2	nM	CHEMBL216819
8.92	Ki	1.2	nM	CHEMBL439753
8.92	IC50	1.2	nM	CHEMBL430648
8.89	IC50	1.29	nM	CHEMBL595807
8.86	IC50	1.38	nM	CHEMBL417149
8.85	Ki	1.4	nM	CHEMBL179503
8.80	IC50	1.6	nM	CHEMBL417149
8.77	IC50	1.7	nM	CHEMBL417149
8.77	IC50	1.7	nM	CHEMBL216071
8.74	IC50	1.8	nM	CHEMBL352426
8.72	Ki	1.9	nM	CHEMBL387041
8.70	EC50	2	nM	CHEMBL5289751
8.66	IC50	2.2	nM	CHEMBL417149
8.64	EC50	2.3	nM	CHEMBL456593
8.64	IC50	2.3	nM	CHEMBL100588
8.63	IC50	2.32	nM	CHEMBL594384
8.62	IC50	2.4	nM	CHEMBL216819
8.62	IC50	2.4	nM	CHEMBL384023
8.62	IC50	2.4	nM	CHEMBL293034
8.62	IC50	2.4	nM	CHEMBL606626
8.60	IC50	2.5	nM	CHEMBL439753
8.59	IC50	2.6	nM	CHEMBL3359197
8.54	IC50	2.9	nM	CHEMBL3359202
8.52	IC50	3	nM	CHEMBL420407
8.52	IC50	3	nM	CHEMBL2086889
8.52	IC50	3	nM	CHEMBL60671
8.52	IC50	2.999	nM	CHEMBL60671
8.51	IC50	3.1	nM	CHEMBL3133146
8.51	IC50	3.1	nM	CHEMBL60671
8.51	IC50	3.1	nM	CHEMBL1762353
8.49	Ki	3.2	nM	CHEMBL225647
8.48	IC50	3.3	nM	CHEMBL603644
8.48	IC50	3.3	nM	CHEMBL1762350
8.46	IC50	3.5	nM	CHEMBL430648

PubChem BioAssay actives

1565 with measured affinity, of 2700 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4S)-4-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-5-[[(2S)-1-[[(2S)-1-carboxy-4-[[2-[4-(dimethylamino)phenyl]-1,3-benzoxazol-5-yl]amino]-3-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	1674214: Inhibition of caspase-3 (unknown origin) using Ac-DEVD-AMCA as substrate incubated for 5 mins by Dixon plot analysis	ki	0.0001	uM
(3S)-3-[2-[5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methylamino]-2-oxopyrazin-1-yl]butanoylamino]-5-[[methyl(pentyl)amino]methylamino]-4-oxopentanoic acid	241557: Inhibitory concentration against recombinant human caspase-3 in neuronal precursor (NT2) cells	ic50	0.0001	uM
1-[[4-(2-fluoroethoxy)phenyl]methyl]-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	271887: Binding affinity to human caspase 3	ki	0.0002	uM
(4S)-4-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-5-[[(2S)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	1795223: Fluorometric Assay from Article 10.1074/jbc.273.49.32608: “Inhibition of human caspases by peptide-based and macromolecular inhibitors.”	ki	0.0002	uM
(3S)-3-[[(2S)-2-[3-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-2-oxo-1-pyridinyl]butanoyl]amino]-5-benzylsulfanyl-4-oxopentanoic acid	241557: Inhibitory concentration against recombinant human caspase-3 in neuronal precursor (NT2) cells	ic50	0.0003	uM
5-[(2S)-2-[(2,4-difluorophenoxy)methyl]pyrrolidin-1-yl]sulfonyl-1-[[1-(2-fluoroethyl)triazol-4-yl]methyl]indole-2,3-dione	389836: Inhibition of human recombinant caspase 3 assessed as accumulation of 7-amino-4-methylcoumarin substrate	ec50	0.0005	uM
2-[4-[[5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl-2,3-dioxoindol-1-yl]methyl]phenoxy]ethyl 4-methylbenzenesulfonate	271887: Binding affinity to human caspase 3	ki	0.0008	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-4-carboxybutanoyl]amino]-3-methylbutanoyl]amino]-4-oxo-7-phenylheptanoic acid	1796493: Caspase Inhibition Assay from Article 10.1021/jm0305523: “Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis.”	ic50	0.0008	uM
N-(4-morpholin-4-ylphenyl)-3-oxo-1,2-benzothiazole-2-carboxamide	1125749: Inhibition of human recombinant caspase-3 using Ac-LDEVD-AMC as substrate after 10 mins by fluorescence assay	ic50	0.0011	uM
5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl-1-methylindole-2,3-dione	271887: Binding affinity to human caspase 3	ki	0.0012	uM
1-[(4-iodophenyl)methyl]-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	271887: Binding affinity to human caspase 3	ki	0.0012	uM
(4S)-4-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-5-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	49512: Inhibitory activity against human Caspase-3 using Ac-AspGluValAsp as substrate	ic50	0.0012	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	0.0012	uM
8-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylspiro[2,4-dihydropyrimido[1,2-a]indole-3,1’-cyclobutane]-10-one	1799299: Caspase-3 Inhibition Assay from Article 10.1016/j.bmc.2009.09.036: “3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3.”	ic50	0.0013	uM
3-[2-[5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methylamino]-2-oxopyrazin-1-yl]butanoylamino]-5-[methyl(pentyl)amino]-4-oxopentanoic acid;hydrochloride	238851: Inhibitory concentration against recombinant human caspase-3 in neuronal precursor (NT2) cells	ki	0.0014	uM
(3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-2-benzamido-3-carboxypropanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]-4-oxo-7-phenylheptanoic acid	1796494: Caspase Inhibition Assay from Article 10.1016/j.bmcl.2003.10.064: “Discovery of novel aspartyl ketone dipeptides as potent and selective caspase-3 inhibitors.”	ic50	0.0018	uM
1-[[4-[tert-butyl(dimethyl)silyl]oxyphenyl]methyl]-5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	271887: Binding affinity to human caspase 3	ki	0.0019	uM
(2S,4R)-1-[(2S)-2-[[2-[3-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxy]-2-[2-[2-[2-[[2-[(9S)-7-(4-chlorophenyl)-4,5,13-trimethyl-3-thia-1,8,11,12-tetrazatricyclo[8.3.0.02,6]trideca-2(6),4,7,10,12-pentaen-9-yl]acetyl]amino]ethoxy]ethoxy]ethoxymethyl]-2-methylpropoxy]acetyl]amino]-3,3-dimethylbutanoyl]-4-hydroxy-N-[[4-(4-methyl-1,3-thiazol-5-yl)phenyl]methyl]pyrrolidine-2-carboxamide	1939901: Activation of caspase 3/7 in human 22Rv1 cells by Caspase-Glo reagent based analysis	ec50	0.0020	uM
8-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylspiro[2,4-dihydropyrimido[1,2-a]indole-3,1’-cyclopentane]-10-one	1799299: Caspase-3 Inhibition Assay from Article 10.1016/j.bmc.2009.09.036: “3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3.”	ic50	0.0023	uM
1-[(4-fluorophenyl)methyl]-5-[(2S)-2-(oxan-4-yloxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	389836: Inhibition of human recombinant caspase 3 assessed as accumulation of 7-amino-4-methylcoumarin substrate	ec50	0.0023	uM
(4S)-5-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-(phenylmethoxycarbonylamino)pentanoic acid	49532: Inhibitory concentration of compound required against Caspase-3 compared to acylated dipeptides	ic50	0.0023	uM
3,3-dimethyl-8-[(2S)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonyl-2,4-dihydropyrimido[1,2-a]indol-10-one	1799299: Caspase-3 Inhibition Assay from Article 10.1016/j.bmc.2009.09.036: “3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3.”	ic50	0.0024	uM
1-methyl-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	375062: Inhibition of human recombinant caspase 3 assessed as accumulation of cleaved fluorogenic 7-amino-4-methylcoumarin after 10 mins	ic50	0.0024	uM
7-bromo-1-(4-hydroxybutyl)-5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	1170192: Inhibition of human recombinant caspase 3 using Ac-DEVD-AMC substrate assessed as accumulation of cleaved fluorogenic product	ic50	0.0026	uM
1-butyl-7-fluoro-5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	1170192: Inhibition of human recombinant caspase 3 using Ac-DEVD-AMC substrate assessed as accumulation of cleaved fluorogenic product	ic50	0.0029	uM
(3S)-3-[[(2S,11S)-11-[[(2S)-2-acetamido-4-methoxy-4-oxobutanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-5-benzylsulfanyl-4-oxopentanoic acid	49529: Inhibitory concentration of compound against caspase-3	ic50	0.0030	uM
(3S)-3-[[(2S,11S)-11-[[(2S)-2-acetamido-3-carboxypropanoyl]amino]-12-oxo-1-azatricyclo[6.4.1.04,13]trideca-4,6,8(13)-triene-2-carbonyl]amino]-5-benzylsulfanyl-4-oxopentanoic acid	1796493: Caspase Inhibition Assay from Article 10.1021/jm0305523: “Reducing the peptidyl features of caspase-3 inhibitors: a structural analysis.”	ic50	0.0030	uM
1-ethyl-3-(4-methoxyphenyl)-6-methylpyrimido[5,4-e][1,2,4]triazine-5,7-dione	683882: Inhibition of caspase3	ic50	0.0030	uM
tert-butyl 2-[2,3-dioxo-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylindol-1-yl]acetate	431515: Inhibition of caspase 3 in human SK-N-SH cells assessed as accumulation of fluorogenic 7-amino-4-methyl coumarin by fluorometric assay	ic50	0.0030	uM
1-[[4-(2-fluoroethoxy)phenyl]methyl]-5-[(2S)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	591187: Inhibition of human caspase 3 by fluorometric assay	ic50	0.0031	uM
(3S)-3-acetamido-4-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid	281982: Inhibition of human caspase 3 expressed in Escherichia coli	ki	0.0032	uM
8-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonylspiro[2,4-dihydropyrimido[1,2-a]indole-3,1’-cyclobutane]-10-one	1799299: Caspase-3 Inhibition Assay from Article 10.1016/j.bmc.2009.09.036: “3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3.”	ic50	0.0033	uM
1-[(4-methoxyphenyl)methyl]-5-[(2S)-2-(pyridin-3-yloxymethyl)azetidin-1-yl]sulfonylindole-2,3-dione	591187: Inhibition of human caspase 3 by fluorometric assay	ic50	0.0033	uM
(4S)-4-[[(2R)-2-acetamido-2-carboxyacetyl]amino]-5-[[(2S)-1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-5-oxopentanoic acid	49532: Inhibitory concentration of compound required against Caspase-3 compared to acylated dipeptides	ic50	0.0035	uM
1-[(4-bromophenyl)methyl]-5-[(2S)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	292076: Inhibition of human recombinant caspase 3	ic50	0.0036	uM
1-(4-fluoro-3-hydroxybutyl)-5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	375062: Inhibition of human recombinant caspase 3 assessed as accumulation of cleaved fluorogenic 7-amino-4-methylcoumarin after 10 mins	ic50	0.0036	uM
1-[[4-(2-fluoroethoxy)phenyl]methyl]-5-[(2S)-2-(pyridin-3-yloxymethyl)azetidin-1-yl]sulfonylindole-2,3-dione	591187: Inhibition of human caspase 3 by fluorometric assay	ic50	0.0036	uM
(4S)-5-[[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-naphthalen-1-yloxy-5-oxopentanoic acid	49531: Inhibition of Caspase-3	ic50	0.0038	uM
1-[(4-methoxyphenyl)methyl]-5-[(2S)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	256994: Inhibitory activity against caspase 3 using Ac-DEVD-AMC substrate	ic50	0.0039	uM
1-[(4-hydroxyphenyl)methyl]-5-[(2S)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	292076: Inhibition of human recombinant caspase 3	ic50	0.0039	uM
4-methyl-8-morpholin-4-ylsulfonyl-2-(1,3,5-trimethylpyrazol-4-yl)pyrrolo[3,4-c]quinoline-1,3-dione	1796448: Caspase Inhibition Assay from Article 10.1016/j.bmcl.2005.02.027: “1,3-Dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines as potent caspase-3 inhibitors.”	ic50	0.0040	uM
1-[(4-hydroxyphenyl)methyl]-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	271887: Binding affinity to human caspase 3	ki	0.0040	uM
5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl-1-(pyridin-4-ylmethyl)indole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ic50	0.0042	uM
1-[(4-methylsulfanylphenyl)methyl]-5-[(2S)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	1796431: Caspase Inhibition Assay from Article 10.1021/jm0506625: “N-benzylisatin sulfonamide analogues as potent caspase-3 inhibitors: synthesis, in vitro activity, and molecular modeling studies.”	ic50	0.0044	uM
8-[(2S)-2-[(5-chloro-3-pyridinyl)oxymethyl]pyrrolidin-1-yl]sulfonyl-3,3-dimethyl-2,4-dihydropyrimido[1,2-a]indol-10-one	1799299: Caspase-3 Inhibition Assay from Article 10.1016/j.bmc.2009.09.036: “3,4-Dihydropyrimido(1,2-a)indol-10(2H)-ones as potent non-peptidic inhibitors of caspase-3.”	ic50	0.0044	uM
1-[[1-(2-fluoroethyl)triazol-4-yl]methyl]-5-[(2S)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	591187: Inhibition of human caspase 3 by fluorometric assay	ic50	0.0045	uM
5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl-1-prop-2-enylindole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ic50	0.0046	uM
7-chloro-1-(3-fluoropropyl)-5-[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	1170192: Inhibition of human recombinant caspase 3 using Ac-DEVD-AMC substrate assessed as accumulation of cleaved fluorogenic product	ic50	0.0048	uM
1-butyl-5-[(2S)-2-(2-fluoroethoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	740441: Inhibition of human recombinant caspase 3 assessed as decrease in AMC release using Ac-Asp-Glu-Val-Asp-AMC as substrate preincubated with enzyme for 10 mins prior to substrate addition measured after 10 mins by fluorescence microplate analysis	ic50	0.0048	uM
1-[(4-methoxyphenyl)methyl]-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonylindole-2,3-dione	271887: Binding affinity to human caspase 3	ki	0.0048	uM

CTD chemical–gene interactions

2068 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases reaction, decreases reaction, increases degradation, decreases response to substance, affects cotreatment (+12 more)	162
Cisplatin	decreases reaction, increases activity, decreases response to substance, increases reaction, decreases cleavage (+9 more)	124
Acetylcysteine	affects cotreatment, affects binding, increases response to substance, decreases reaction, increases cleavage (+7 more)	123
Resveratrol	decreases reaction, increases expression, increases cleavage, decreases cleavage, affects cotreatment (+12 more)	105
Doxorubicin	increases reaction, decreases activity, increases expression, increases response to substance, decreases reaction (+14 more)	97
Quercetin	decreases reaction, increases cleavage, increases expression, increases response to substance, affects cleavage (+7 more)	91
Hydrogen Peroxide	increases cleavage, decreases abundance, affects expression, decreases cleavage, increases reaction (+7 more)	60
Bortezomib	increases phosphorylation, affects reaction, increases cleavage, decreases reaction, increases reaction (+6 more)	58
sodium arsenite	decreases expression, affects cleavage, affects cotreatment, decreases cleavage, increases cleavage (+11 more)	46
Fluorouracil	increases activity, increases cleavage, increases reaction, affects reaction, decreases expression (+7 more)	46
1-Methyl-4-phenylpyridinium	affects reaction, increases activity, increases expression, affects response to substance, affects cleavage (+5 more)	46
pyrazolanthrone	decreases reaction, decreases expression, increases activity, increases expression, affects cotreatment (+3 more)	44
Paclitaxel	increases cleavage, decreases expression, affects cotreatment, increases activity, affects reaction (+3 more)	42
Paraquat	decreases reaction, increases activity, affects cotreatment, increases reaction, increases abundance (+5 more)	35
Plant Extracts	increases expression, increases activity, decreases expression, increases abundance, affects cotreatment (+2 more)	35
Curcumin	increases expression, increases reaction, affects binding, decreases activity, decreases reaction (+5 more)	34
Staurosporine	increases activity, increases reaction, decreases reaction, increases expression, increases cleavage (+2 more)	33
Tretinoin	affects response to substance, affects cleavage, increases reaction, increases expression, affects cotreatment (+3 more)	32
3-methyladenine	affects cotreatment, increases cleavage, decreases reaction, increases reaction, increases degradation (+4 more)	31
Etoposide	increases reaction, increases expression, increases response to substance, decreases reaction, affects cotreatment (+6 more)	31
SB 203580	increases activity, increases cleavage, affects cotreatment, increases abundance, increases reaction (+3 more)	30
benzoylcarbonyl-aspartyl-glutamyl-valyl-aspartyl-fluoromethyl ketone	decreases reaction, increases cleavage, increases expression, decreases activity, decreases response to substance (+3 more)	30
Vorinostat	increases abundance, decreases reaction, increases activity, increases cleavage, increases reaction (+3 more)	30
benzyloxycarbonyl-valyl-alanyl-aspartic acid	increases cleavage, increases expression, increases reaction, increases response to substance, increases activity (+3 more)	29
Rotenone	increases cleavage, increases secretion, affects cotreatment, increases reaction, increases expression (+4 more)	27
Cadmium Chloride	decreases reaction, increases activity, increases abundance, decreases expression, decreases activity (+6 more)	27
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	increases cleavage, affects cotreatment, decreases reaction, increases abundance, increases localization (+6 more)	24
Cadmium	affects reaction, decreases reaction, increases activity, affects cotreatment, affects binding (+7 more)	23
bisphenol A	increases expression, increases cleavage, decreases activity, decreases reaction, increases activity (+3 more)	21
Sorafenib	decreases reaction, increases cleavage, decreases expression, increases reaction, increases activity (+3 more)	21

ChEMBL screening assays

349 unique, capped per target: 327 binding, 16 functional, 4 toxicity, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1004121	Binding	Inhibition of human recombinant caspase 3 assessed as accumulation of cleaved fluorogenic 7-amino-4-methylcoumarin after 10 mins	Fluorinated isatin derivatives. Part 2. New N-substituted 5-pyrrolidinylsulfonyl isatins as potential tools for molecular imaging of caspases in apoptosis. — J Med Chem
CHEMBL1738414	Functional	PUBCHEM_BIOASSAY: Dose Response confirmation of inhibitors of Sentrin-specific proteases (SENPs) using a Caspase-3 Selectivity assay. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID2540, AID2599, AID434973, AI	PubChem BioAssay data set
CHEMBL3603478	ADMET	Prodrug conversion assessed as recombinant human caspase-3-mediated 6-(3-(2-aminoethylthio)-2,5-dioxopyrrolidin-1-yl)-N-((2S,3S,4S,6R)-3-hydroxy-2-methyl-6-((1S,3S)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-1,2,3,4,6,11-he	Optimization of a Stable Linker Involved DEVD Peptide-Doxorubicin Conjugate That Is Activated upon Radiation-Induced Caspase-3-Mediated Apoptosis. — J Med Chem

Cellosaurus cell lines

11 cell lines: 10 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1M4	Abcam HeLa CASP3 KO	Cancer cell line	Female
CVCL_B7WE	Abcam Raji CASP3 KO	Cancer cell line	Male
CVCL_B9WX	Abcam THP-1 CASP3 KO	Cancer cell line	Male
CVCL_C6YY	Abcam PC-3 CASP3 KO	Cancer cell line	Male
CVCL_D6AG	HyCyte A-549 KO-hCASP3	Cancer cell line	Male
CVCL_D7LS	Ubigene A-549 CASP3 KO	Cancer cell line	Male
CVCL_D8IH	Ubigene HCT 116 CASP3 KO	Cancer cell line	Male
CVCL_D9B2	Ubigene HEK293 CASP3 KO	Transformed cell line	Female
CVCL_D9ZE	Ubigene HeLa CASP3 KO	Cancer cell line	Female
CVCL_KT45	HeLa SilenciX Caspase 3	Cancer cell line	Female

Clinical trials (associated diseases)

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