CASP9

Summary

CASP9 (caspase 9, HGNC:1511) is a protein-coding gene on chromosome 1p36.21, encoding Caspase-9 (P55211). Involved in the activation cascade of caspases responsible for apoptosis execution.

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family. Sequential activation of caspases plays a central role in the execution-phase of cell apoptosis. Caspases exist as inactive proenzymes which undergo proteolytic processing at conserved aspartic residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein can undergo autoproteolytic processing and activation by the apoptosome, a protein complex of cytochrome c and the apoptotic peptidase activating factor 1; this step is thought to be one of the earliest in the caspase activation cascade. This protein is thought to play a central role in apoptosis and to be a tumor suppressor. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 842 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 111 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001229

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1511
Approved symbol	CASP9
Name	caspase 9
Location	1p36.21
Locus type	gene with protein product
Status	Approved
Aliases	MCH6, ICE-LAP6, APAF-3, PPP1R56
Ensembl gene	ENSG00000132906
Ensembl biotype	protein_coding
OMIM	602234
Entrez	842

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000333868, ENST00000348549, ENST00000375890, ENST00000400777, ENST00000424908, ENST00000440484, ENST00000447522, ENST00000469637, ENST00000474305, ENST00000546424, ENST00000546969, ENST00000922642

RefSeq mRNA: 3 — MANE Select: NM_001229 NM_001229, NM_001278054, NM_032996

CCDS: CCDS158, CCDS159, CCDS59995

Canonical transcript exons

ENST00000333868 — 9 exons

Exon	Start	End
ENSE00002686918	15524069	15524215
ENSE00003469239	15505990	15506079
ENSE00003485753	15504611	15504758
ENSE00003488698	15518110	15518395
ENSE00003501673	15506899	15507075
ENSE00003506519	15507873	15507907
ENSE00003572221	15493892	15494001
ENSE00003784959	15495273	15495452
ENSE00003843812	15491401	15493035

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 95.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.9275 / max 169.9771, expressed in 1752 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10456	10.1829	1717
10458	0.5401	298
10457	0.1343	39
10459	0.0527	17
10455	0.0175	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	95.93	gold quality
right uterine tube	UBERON:0001302	95.02	gold quality
left ovary	UBERON:0002119	94.66	gold quality
secondary oocyte	CL:0000655	93.03	gold quality
right ovary	UBERON:0002118	92.58	gold quality
pituitary gland	UBERON:0000007	92.33	gold quality
adenohypophysis	UBERON:0002196	92.11	gold quality
ovary	UBERON:0000992	91.91	gold quality
lower esophagus mucosa	UBERON:0035834	91.67	gold quality
right testis	UBERON:0004534	90.86	gold quality
apex of heart	UBERON:0002098	90.70	gold quality
left testis	UBERON:0004533	90.29	gold quality
left lobe of thyroid gland	UBERON:0001120	90.19	gold quality
right lobe of thyroid gland	UBERON:0001119	89.91	gold quality
thyroid gland	UBERON:0002046	89.81	gold quality
adrenal cortex	UBERON:0001235	89.57	gold quality
right adrenal gland cortex	UBERON:0035827	89.56	gold quality
mucosa of urinary bladder	UBERON:0001259	89.43	gold quality
oocyte	CL:0000023	89.33	gold quality
left adrenal gland cortex	UBERON:0035825	89.24	gold quality
right adrenal gland	UBERON:0001233	89.10	gold quality
adrenal gland	UBERON:0002369	89.04	gold quality
parotid gland	UBERON:0001831	88.92	gold quality
body of pancreas	UBERON:0001150	88.68	gold quality
left adrenal gland	UBERON:0001234	88.67	gold quality
left uterine tube	UBERON:0001303	88.64	gold quality
buccal mucosa cell	CL:0002336	88.59	gold quality
testis	UBERON:0000473	88.56	gold quality
male germ cell	CL:0000015	88.06	gold quality
sperm	CL:0000019	88.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	21.39

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DDIT3, FOS, FOXO1, FOXO3, FOXP3, IRF1, MYC, MYCN, NFKB1, NKX3-1, PARP1, RARA, RELA, TP53

miRNA regulators (miRDB)

56 targeting CASP9, 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-126-5P	100.00	72.71	3180
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-548B-3P	99.38	67.26	1000
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-130A-5P	99.33	70.26	2623

Literature-anchored findings (GeneRIF, showing 40)

• regulation of alternative splicing in lung adenocarcinoma cells by de novo ceramide (PMID:11801602)
• Caspase-9 at chromosome 1 reveal rare allelic variants in neuroblastoma tumors (PMID:11870543)
• inhibition of caspase-9 activity represents another mechanism of acquired cisplatin resistance (PMID:11905052)
• Activation of caspase-9 is required for UV-induced apoptosis of human keratinocytes (PMID:11919192)
• activation by an alternative mechanism virally infected cells beside the well characterized pathways via death receptors or mitochondrial cytochrome c release (PMID:12021264)
• Down-regulation of caspase-9 is involved during serum-factor dependent phagocytosis of platelets by monocytes. (PMID:12055227)
• Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. (PMID:12096338)
• Pro-CASP9 moved from the nucleus to the mitochondria of U937 cells during TPA-induced differentiation. (PMID:12145703)
• processing and activation upon dsRNA-dependent protein kinase expression (PMID:12372609)
• Data suggest that the expression levels of caspase 9 or caspase 9S do not play a major role in determining vulnerability to apoptosis in human astrocytoma cells. (PMID:12393263)
• blocks apocytochrome c activation and Bax-induced apoptosis (PMID:12393884)
• Presentation of nitric oxide regulates monocyte survival through effects on this enzyme and caspase-3 activation. (PMID:12566444)
• single amino acid substitutions at the dimer interface abrogate the activity of caspases-8 and -9 (PMID:12620239)
• aggregation of multiple procaspase-9 molecules can induce their activation independent of the apoptosome (PMID:12637514)
• Smac-induced apoptosis proceeds via a pathway mediated by caspase-9 that can be inhibited by zLEHD-fmk and overexpression of XIAP protein. (PMID:12749848)
• caspase-9 redistribution is a regulated process and requires the activity of a caspase other than the caspase-9- this is required to control the activity of caspase-9 (PMID:12782307)
• CASP 9 by itself can activate caspase 7 in the absence of the caspase 3-dependent pathway in TNF-alpha-induced apoptosis (PMID:12804035)
• caspase-9 is activated by reactive oxygen species (ROS) without involvement of cytochrome c release in hypoxic injury (PMID:12914932)
• caspase 9 is not critical for ultraviolet ray-induced apoptosis in tumor cells (PMID:12954616)
• AMF regulates expression of Apaf-1 and caspase-9 genes via a complex signaling pathway and indirectly regulates formation of the apoptosome. (PMID:14566819)
• Caspase-9 is activated in oxidized low-density lipoprotein (ox-LDL) induces apoptosis in endothelial cells. (PMID:14684629)
• S-nitrosation regulates activation of endogenous procaspase-9 in HT-29 cells (PMID:14701803)
• procaspase-9 is dimerized and processed by redox stress in mitochondria (PMID:14747474)
• RGDS directly binds and activates caspases 8 and 9, inhibits chemotaxis, and induces apoptosis of HUVECs with a mechanism independent from its antiadhesive effect. (PMID:14982875)
• caspase-9 activation in human disease can play a prominent role in localized cellular degenerative processes without causing nuclear or cell death. (PMID:14991812)
• the functional apoptosome complex in apoptotic cells consists primarily of Apaf-1 and processed caspase-9 (PMID:14993223)
• BCR-signal causes Bax translocation, followed by mitochondrial depolarization, and cytC release; subsequent caspase-9 activation can account for events further downstream (PMID:15214043)
• required for Parvovirus B19 virus-induced apoptosis in primary hepatocytes and hepatocellular carcinoma cell line HepG2 (PMID:15220451)
• Low-dose 5-aza-2’-deoxycytidine (DAC) induced enhancement of apoptosis mediated by Adenovirus-p53 infection, and ectopic overexpression of procaspase-9. (PMID:15273730)
• caspase-9 binds to NAIP in an ATP-dependent manner (PMID:15280366)
• Apollon binds to, ubiquitinates and facilitates proteasomal degradation of SMAC and caspase-9, results suggesting that Apollon has an essential function in preventing SMAC-induced apoptosis (PMID:15300255)
• These data suggest that increased proneness to caspase activation in lymphocytes could reflect an ongoing systemic response in neurodegenerative disease with pathogenetic implications. (PMID:15473998)
• ILP2 is an unstable protein, and cannot inhibit caspase 9 in a physiological way on its own; possibly ILP2 requires assistance from unidentified cellular factors to be an effective inhibitor of apoptosis in vivo (PMID:15485395)
• results suggest that ML-IAP might regulate apoptosis by sequestering Smac and preventing it from antagonizing XIAP-mediated inhibition of caspases, rather than by direct inhibition of caspases (PMID:15485396)
• Dopamine[DA] neurons were labeled and transduced with dominant negative Casp9. Progressive DA neuron lesion was induced by striatal 6-OHDA injection.Inhibiting apoptosis at caspase-9 is protective in vitro, but not in vivo. (PMID:15629764)
• caspase-9 autoprocessing is regulated by c-Abl in the apoptotic response to genotoxic stress. (PMID:15657060)
• Gossypol induced complete cytochrome c release from mitochondria amd increased caspases-3 and -9 activity in large cell lymphoma cells. (PMID:15657349)
• Role for caspase-9 mediated cleavage of Raf-1 in the negative feedback regulation of hematopoietic cell apoptosis induced by growth factor withdrawal. (PMID:15674327)
• Protein kinase A regulates caspase-9 activation by Apaf-1 downstream of cytochrome c (PMID:15703181)
• OGG1 targeted to mitochondria reduces the activation of caspase-9 (PMID:15811855)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp9	ENSDARG00000004325
mus_musculus	Casp9	ENSMUSG00000028914
rattus_norvegicus	Casp9_v1	ENSRNOG00000012944
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), CASP2 (ENSG00000106144), CASP1 (ENSG00000137752), CASP5 (ENSG00000137757), CASP6 (ENSG00000138794), CASP3 (ENSG00000164305), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CASP4 (ENSG00000196954), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Protein

Protein identifiers

Caspase-9 — P55211 (reviewed: P55211)

Alternative names: Apoptotic protease Mch-6, Apoptotic protease-activating factor 3, ICE-like apoptotic protease 6

All UniProt accessions (8): A0A087WX72, P55211, F8VVS7, F8VWA5, H0Y3S8, H0Y6Y2, Q5JRU2, Q5JRU8

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the activation cascade of caspases responsible for apoptosis execution. Binding of caspase-9 to Apaf-1 leads to activation of the protease which then cleaves and activates effector caspases caspase-3 (CASP3) or caspase-7 (CASP7). Promotes DNA damage-induced apoptosis in a ABL1/c-Abl-dependent manner. Proteolytically cleaves poly(ADP-ribose) polymerase (PARP). Cleaves BIRC6 following inhibition of BIRC6-caspase binding by DIABLO/SMAC. Lacks activity is an dominant-negative inhibitor of caspase-9.

Subunit / interactions. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 35 kDa (p35) and a 10 kDa (p10) subunit. Caspase-9 and APAF1 bind to each other via their respective NH2-terminal CED-3 homologous domains in the presence of cytochrome C and ATP. Interacts (inactive form) with EFHD2. Interacts with HAX1. Interacts with BIRC2/c-IAP1, XIAP/BIRC4, BIRC5/survivin, BIRC6/bruce and BIRC7/livin. Interacts with ABL1 (via SH3 domain); the interaction is direct and increases in the response of cells to genotoxic stress and ABL1/c-Abl activation. Interacts with BCL2L10. Interacts with NleF from pathogenic E.coli.

Tissue specificity. Ubiquitous, with highest expression in the heart, moderate expression in liver, skeletal muscle, and pancreas. Low levels in all other tissues. Within the heart, specifically expressed in myocytes.

Post-translational modifications. Cleavages at Asp-315 by granzyme B and at Asp-330 by caspase-3 generate the two active subunits. Caspase-8 and -10 can also be involved in these processing events. Phosphorylated at Thr-125 by MAPK1/ERK2. Phosphorylation at Thr-125 is sufficient to block caspase-9 processing and subsequent caspase-3 activation. Phosphorylation on Tyr-153 by ABL1/c-Abl; occurs in the response of cells to DNA damage. (Microbial infection) ADP-riboxanation by C.violaceum CopC blocks CASP9 processing, preventing CASP9 activation and ability to mediate intrinsic apoptosis. Ubiquitinated by BIRC6; this activity is inhibited by DIABLO/SMAC.

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

Miscellaneous. May function as an endogenous apoptotic inhibitor, inhibits the BAX-mediated cleavage of procaspase-3.

Similarity. Belongs to the peptidase C14A family.

Isoforms (4)

UniProt ID	Names	Canonical?
P55211-1	1, 9L, Alpha	yes
P55211-2	2, 9S, Beta
P55211-3	3, Gamma
P55211-4	4

RefSeq proteins (3): NP_001220, NP_001264983, NP_127463 (=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
IPR042147	CARD_CASP9	Domain

Pfam: PF00619, PF00656

Enzyme classification (BRENDA):

• EC 3.4.22.62 — caspase-9 (BRENDA: 11 organisms, 139 substrates, 67 inhibitors, 7 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ACETYL-LEHD-7-AMIDO-4-TRIFLUOROMETHYL COUMARIN	0.466–0.686	2
ACETYL-LEHD-7-AMIDO-4-TRIFLUOROMETHYLCOUMARIN	0.466–0.686	2
ACETYL-VEHD-7-AMIDO-4-METHYLCOUMARIN	0.408–0.78	2
PROCASPASE-3	0.139	1

UniProt features (70 total): helix 16, strand 15, sequence variant 11, modified residue 6, turn 5, splice variant 4, sequence conflict 3, propeptide 2, chain 2, mutagenesis site 2, active site 2, domain 1, region of interest 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
3D9T	X-RAY DIFFRACTION	1.5
4RHW	X-RAY DIFFRACTION	2.1
1NW9	X-RAY DIFFRACTION	2.4
9R44	X-RAY DIFFRACTION	2.46
3YGS	X-RAY DIFFRACTION	2.5
1JXQ	X-RAY DIFFRACTION	2.8
2AR9	X-RAY DIFFRACTION	2.8
5WVC	X-RAY DIFFRACTION	2.99
3V3K	X-RAY DIFFRACTION	3.49
5JUY	ELECTRON MICROSCOPY	4.1
5WVE	ELECTRON MICROSCOPY	4.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55211-F1	80.86	0.55

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): 237; 287

Post-translational modifications (6): 302, 307, 310, 355, 125, 153

Mutagenesis-validated functional residues (2):

Position	Phenotype
153	inhibits tyrosine phosphorylation. reduces caspase-9 subunit p35 formation in response to genotoxic stress. attenuates a
355	abolished adp-riboxanation by c.violaceum copc.

Function

Pathways and Gene Ontology

Reactome pathways

25 pathways

ID	Pathway
R-HSA-111458	Formation of apoptosome
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-168638	NOD1/2 Signaling Pathway
R-HSA-198323	AKT phosphorylates targets in the cytosol
R-HSA-418889	Caspase activation via Dependence Receptors in the absence of ligand
R-HSA-5674400	Constitutive Signaling by AKT1 E17K in Cancer
R-HSA-9627069	Regulation of the apoptosome activity
R-HSA-109581	Apoptosis
R-HSA-109606	Intrinsic Pathway for Apoptosis
R-HSA-111461	Cytochrome c-mediated apoptotic response
R-HSA-111469	SMAC, XIAP-regulated apoptotic response
R-HSA-111471	Apoptotic factor-mediated response
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
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-2219528	PI3K/AKT Signaling in Cancer
R-HSA-5357769	Caspase activation via extrinsic apoptotic signalling pathway
R-HSA-5357801	Programmed Cell Death
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-9006925	Intracellular signaling by second messengers

MSigDB gene sets: 366 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, REACTOME_INNATE_IMMUNE_SYSTEM, CHIBA_RESPONSE_TO_TSA_UP, GOBP_RESPONSE_TO_ESTRADIOL, REACTOME_NOD1_2_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_UV, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, NAGASHIMA_NRG1_SIGNALING_UP, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_METAL_ION

GO Biological Process (30): response to hypoxia (GO:0001666), kidney development (GO:0001822), response to ischemia (GO:0002931), apoptotic process (GO:0006915), DNA damage response (GO:0006974), intrinsic apoptotic signaling pathway in response to DNA damage (GO:0008630), protein processing (GO:0016485), platelet formation (GO:0030220), response to cobalt ion (GO:0032025), response to estradiol (GO:0032355), response to lipopolysaccharide (GO:0032496), glial cell apoptotic process (GO:0034349), cellular response to UV (GO:0034644), signal transduction in response to DNA damage (GO:0042770), positive regulation of apoptotic process (GO:0043065), positive regulation of neuron apoptotic process (GO:0043525), fibroblast apoptotic process (GO:0044346), response to ethanol (GO:0045471), neuron apoptotic process (GO:0051402), protein maturation (GO:0051604), cellular response to dexamethasone stimulus (GO:0071549), response to indole-3-methanol (GO:0071680), leukocyte apoptotic process (GO:0071887), response to anesthetic (GO:0072347), intrinsic apoptotic signaling pathway (GO:0097193), positive regulation of execution phase of apoptosis (GO:1900119), epithelial cell apoptotic process (GO:1904019), proteolysis (GO:0006508), response to UV (GO:0009411), regulation of apoptotic process (GO:0042981)

GO Molecular Function (10): cysteine-type endopeptidase activity (GO:0004197), enzyme activator activity (GO:0008047), peptidase activity (GO:0008233), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), protease binding (GO:0002020), protein binding (GO:0005515), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787), death domain binding (GO:0070513)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), caspase complex (GO:0008303), protein-containing complex (GO:0032991), apoptosome (GO:0043293)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Cytochrome c-mediated apoptotic response	2
SMAC, XIAP-regulated apoptotic response	2
Apoptotic factor-mediated response	2
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
PIP3 activates AKT signaling	1
Caspase activation via extrinsic apoptotic signalling pathway	1
PI3K/AKT Signaling in Cancer	1
Formation of apoptosome	1
Programmed Cell Death	1
Apoptosis	1
Intrinsic Pathway for Apoptosis	1
Intracellular signaling by second messengers	1
Immune System	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
apoptotic process	4
response to stress	2
DNA damage response	2
response to lipid	2
response to oxygen-containing compound	2
catalytic activity	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
response to decreased oxygen levels	1
animal organ development	1
renal system development	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular response to stress	1
intrinsic apoptotic signaling pathway	1
proteolysis	1
protein maturation	1
myeloid cell differentiation	1
platelet morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to metal ion	1
response to molecule of bacterial origin	1
response to UV	1
cellular response to light stimulus	1
intracellular signal transduction	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
response to alcohol	1
gene expression	1
protein metabolic process	1
endopeptidase activity	1
cysteine-type peptidase activity	1
enzyme regulator activity	1
molecular function activator activity	1
hydrolase activity	1

Protein interactions and networks

STRING

3868 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP9	CYCS	P00001	999
CASP9	APAF1	O14727	999
CASP9	XIAP	P98170	998
CASP9	DIABLO	Q9NR28	964
CASP9	BCL2L1	Q07817	960
CASP9	CASP3	P42574	958
CASP9	TP53	P04637	952
CASP9	BCL2	P10415	938
CASP9	BECN1	Q14457	927
CASP9	BIRC7	Q96CA5	917
CASP9	PARP1	P09874	916
CASP9	BIRC2	Q13490	911
CASP9	AKT1	P31749	887
CASP9	ANXA5	P08758	885
CASP9	MDM2	Q00987	864

IntAct

118 interactions, top by confidence:

A	B	Type	Score
CASP9	XIAP	psi-mi:“MI:0915”(physical association)	0.970
CASP9	XIAP	psi-mi:“MI:0407”(direct interaction)	0.970
XIAP	CASP9	psi-mi:“MI:0915”(physical association)	0.970
XIAP	CASP9	psi-mi:“MI:2364”(proximity)	0.970
CASP9	XIAP	psi-mi:“MI:2364”(proximity)	0.970
CASP9	XIAP	psi-mi:“MI:0914”(association)	0.970
APAF1	CASP9	psi-mi:“MI:0407”(direct interaction)	0.960
CASP9	APAF1	psi-mi:“MI:0407”(direct interaction)	0.960
APAF1	CASP9	psi-mi:“MI:0915”(physical association)	0.960

BioGRID (154): ABL1 (Affinity Capture-Western), ABL1 (Reconstituted Complex), CASP9 (Biochemical Activity), CASP9 (Reconstituted Complex), CASP9 (Co-fractionation), CASP9 (Two-hybrid), CASP9 (Two-hybrid), BIRC7 (Two-hybrid), BIRC8 (Two-hybrid), CASP9 (Affinity Capture-Western), CASP9 (Affinity Capture-Western), CASP9 (Affinity Capture-Western), CASP9 (Affinity Capture-Western), CASP9 (Two-hybrid), CASP9 (Biochemical Activity)

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

60 interactions.

A	Effect	B	Mechanism
MAPK1	“down-regulates activity”	CASP9	phosphorylation
MAPK3	“down-regulates activity”	CASP9	phosphorylation
XIAP	“down-regulates quantity by destabilization”	CASP9	binding
AKT2	down-regulates	CASP9	phosphorylation
NAIP	down-regulates	CASP9	binding
ABL1	up-regulates	CASP9	phosphorylation
CASP3	“up-regulates activity”	CASP9	cleavage
CASP9	“up-regulates activity”	CASP3	cleavage
PRKACA	down-regulates	CASP9	phosphorylation
APAF1	“up-regulates activity”	CASP9	binding
CDK1	down-regulates	CASP9	phosphorylation
PRKCZ	down-regulates	CASP9	phosphorylation
CARD8	down-regulates	CASP9	binding
PPP1CA	up-regulates	CASP9	dephosphorylation
CyclinB/CDK1	down-regulates	CASP9	phosphorylation
PPP1CA	“up-regulates activity”	CASP9	dephosphorylation
AKT1	down-regulates	CASP9	phosphorylation
AKT1	“down-regulates activity”	CASP9	phosphorylation
“Caspase 3 complex”	“up-regulates activity”	CASP9	cleavage
PTMA	down-regulates	CASP9	binding
ANP32A	“up-regulates activity”	CASP9	binding
M	“up-regulates activity”	CASP9
3a	“up-regulates activity”	CASP9
ABL1	“up-regulates activity”	CASP9	phosphorylation
MYCT1	“up-regulates activity”	CASP9

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 24 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
Intrinsic Pathway for Apoptosis	5	86.1×	4e-08
Programmed Cell Death	7	60.3×	4e-10
Apoptosis	6	59.3×	9e-09
Cytokine Signaling in Immune system	5	12.0×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
neuron apoptotic process	6	52.9×	2e-07
positive regulation of protein ubiquitination	5	50.8×	2e-06
regulation of apoptotic process	6	23.8×	6e-06
regulation of cell cycle	5	17.8×	2e-04
positive regulation of canonical NF-kappaB signal transduction	5	17.3×	2e-04
positive regulation of apoptotic process	5	13.5×	5e-04
negative regulation of apoptotic process	7	11.6×	5e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	71
Likely benign	15
Benign	13

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
2446820	NC_000001.10:g.4481271_20530242del	Pathogenic

SpliceAI

1806 predictions. Top by Δscore:

Variant	Effect	Δscore
1:15493887:CTCA:C	donor_loss	1.0000
1:15493888:TCA:T	donor_loss	1.0000
1:15493889:CACCC:C	donor_loss	1.0000
1:15493890:AC:A	donor_gain	1.0000
1:15493891:CC:C	donor_gain	1.0000
1:15495268:CTCA:C	donor_loss	1.0000
1:15495269:TCA:T	donor_loss	1.0000
1:15495270:CA:C	donor_loss	1.0000
1:15495271:A:AG	donor_loss	1.0000
1:15495272:C:CG	donor_loss	1.0000
1:15495448:CTGCT:C	acceptor_gain	1.0000
1:15495449:TGCT:T	acceptor_gain	1.0000
1:15495450:GCT:G	acceptor_gain	1.0000
1:15495451:CT:C	acceptor_gain	1.0000
1:15495451:CTC:C	acceptor_gain	1.0000
1:15495452:TCT:T	acceptor_gain	1.0000
1:15495452:TCTGC:T	acceptor_loss	1.0000
1:15495453:C:CC	acceptor_gain	1.0000
1:15495454:T:A	acceptor_loss	1.0000
1:15504605:GCTTA:G	donor_loss	1.0000
1:15504606:CTTA:C	donor_loss	1.0000
1:15504607:TTA:T	donor_loss	1.0000
1:15504608:TA:T	donor_loss	1.0000
1:15504609:A:C	donor_loss	1.0000
1:15504609:AC:A	donor_gain	1.0000
1:15504609:ACCC:A	donor_gain	1.0000
1:15504610:C:CA	donor_loss	1.0000
1:15504610:CC:C	donor_gain	1.0000
1:15504610:CCCC:C	donor_gain	1.0000
1:15504647:T:TA	donor_gain	1.0000

AlphaMissense

2720 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:15492997:C:A	Q399H	0.990
1:15492997:C:G	Q399H	0.990
1:15495302:T:A	D340V	0.988
1:15507016:G:C	F171L	0.988
1:15507016:G:T	F171L	0.988
1:15507018:A:G	F171L	0.988
1:15493000:T:A	K398N	0.987
1:15493000:T:G	K398N	0.987
1:15504639:C:A	K280N	0.987
1:15504639:C:G	K280N	0.987
1:15493997:A:C	F351L	0.985
1:15493997:A:T	F351L	0.985
1:15493999:A:G	F351L	0.985
1:15506003:G:A	S236F	0.984
1:15507040:G:C	C163W	0.984
1:15492968:T:A	K409I	0.983
1:15506004:A:G	S236P	0.983
1:15518355:A:G	L58P	0.983
1:15504730:A:T	V250D	0.982
1:15495284:G:A	S346F	0.981
1:15504643:G:T	P279H	0.981
1:15506991:G:T	R180S	0.981
1:15504634:A:G	F282S	0.979
1:15506003:G:T	S236Y	0.979
1:15495302:T:G	D340A	0.978
1:15518343:A:G	L62P	0.978
1:15518298:A:G	L77S	0.977
1:15495293:A:T	V343E	0.976
1:15492971:C:G	R408P	0.975
1:15493022:A:T	V391D	0.974

dbSNP variants (sampled 300 via entrez): RS1000025870 (1:15506728 C>T), RS1000046782 (1:15513875 G>C), RS1000143600 (1:15518980 T>C,G), RS1000158133 (1:15520293 G>A), RS1000200065 (1:15502365 T>A), RS1000568073 (1:15514504 C>G,T), RS1000635063 (1:15507785 C>T), RS1000650637 (1:15524727 C>T), RS1000727345 (1:15495811 C>A), RS1000925377 (1:15526814 A>G), RS1001097703 (1:15520281 AT>A), RS1001148117 (1:15491673 T>C), RS1001205450 (1:15526301 G>A,C), RS1001209661 (1:15519778 G>A), RS1001440705 (1:15519164 C>T)

Disease associations

OMIM: gene MIM:602234 | disease phenotypes: MIM:607872

GenCC curated gene-disease

Mondo (1): chromosome 1p36 deletion syndrome (MONDO:0011929)

Orphanet (1): 1p36 deletion syndrome (Orphanet:1606)

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST003372_7	Glomerular filtration rate (creatinine)	2.000000e-09
GCST003401_17	Glomerular filtration rate in non diabetics (creatinine)	5.000000e-09
GCST004292_3	Glomerular filtration rate (creatinine)	1.000000e-09
GCST004860_35	Alcoholic chronic pancreatitis	6.000000e-09
GCST004860_43	Alcoholic chronic pancreatitis	3.000000e-22
GCST004860_47	Alcoholic chronic pancreatitis	3.000000e-06
GCST004860_69	Alcoholic chronic pancreatitis	6.000000e-07
GCST004860_81	Alcoholic chronic pancreatitis	1.000000e-16
GCST004860_92	Alcoholic chronic pancreatitis	3.000000e-06
GCST004860_94	Alcoholic chronic pancreatitis	1.000000e-11
GCST007344_135	Estimated glomerular filtration rate	2.000000e-10
GCST007344_30	Estimated glomerular filtration rate	3.000000e-06
GCST007344_31	Estimated glomerular filtration rate	2.000000e-07
GCST007344_97	Estimated glomerular filtration rate	3.000000e-10
GCST008971_54	Urate levels	8.000000e-09
GCST009733_123	Urinary metabolite levels in chronic kidney disease	6.000000e-31
GCST009733_158	Urinary metabolite levels in chronic kidney disease	1.000000e-44
GCST012020_62	Serum metabolite levels	7.000000e-50
GCST012362_2	Orofacial cleft x maternal periconceptional multivitamin use interaction (2df)	3.000000e-07
GCST012365_1	Orofacial cleft x maternal periconceptional multivitamin use interaction (1df)	9.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0005116	urinary metabolite measurement
EFO:0009116	vitamin supplement exposure measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535362	Chromosome 1p36 Deletion Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2273 (SINGLE PROTEIN), CHEMBL3831289 (PROTEIN FAMILY), CHEMBL3885517 (PROTEIN COMPLEX)

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

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4645983	CASP9		0.00	0
rs4661636	CASP9		0.00	0
rs1052576	CASP9		0.00	0

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
isatin sulfonamide 34 [PMID: 11384246]	Inhibition	6.92	pKi

Binding affinities (BindingDB)

355 measured of 449 human assays (496 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2,5-bis(chloranyl)-3-[2-(dimethylamino)-1,3-thiazol-5-yl]-6-pyrrolidin-1-yl-cyclohexa-2,5-diene-1,4-dione	EC50	210 nM
Z-Asp-(D,L Ala(2’-quinolyl))-Val- Aspphenyl vinylsulfone	IC50	300 nM	US-10167313: Selective caspase inhibitors and uses thereof
8-fluoranylindolo[2,1-b]quinazoline-6,12-dione	IC50	433 nM
(NE)-N-[3-[(4-hydroxyphenyl)amino]-4-oxidanylidene-naphthalen-1-ylidene]-4-methoxy-benzenesulfonamide	IC50	441 nM
MLS002153809	IC50	443 nM
MLS000585839	IC50	453 nM
(4S)-5-[[(2S)-1-[[(E,2S)-1-carboxy-4-methylsulfonylbut-3-en-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-[[(2S)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-5-oxopentanoic acid	IC50	500 nM	US-9045524: Selective caspase inhibitors and uses thereof
4-[(E)-[3-(2-methylanilino)-4-oxo-1-naphthalenylidene]amino]sulfonylbenzoic acid	IC50	522 nM
3-[[(4E)-1-keto-4-tosylimino-2-naphthyl]amino]benzoic acid	IC50	524 nM
2-amino-4-[4-(4-chlorobenzyl)oxy-3-methoxy-phenyl]-6-phenyl-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester	EC50	580 nM
4-[(E)-[3-(2-fluoroanilino)-4-keto-1-naphthylidene]amino]sulfonylbenzoic acid	IC50	638 nM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-methylbutanoyl]amino]-5-methylsulfonylpent-4-enoic acid	IC50	700 nM	US-9045524: Selective caspase inhibitors and uses thereof
SMR000186252	IC50	707 nM
cid_4422714	IC50	798 nM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-2-(2,3-dihydro-1H-inden-2-yl)acetyl]amino]-3-methylbutanoyl]amino]-5-methylsulfonylpent-4-enoic acid	IC50	900 nM	US-9045524: Selective caspase inhibitors and uses thereof
3-[[(4E)-4-(2,4-dimethylphenyl)sulfonylimino-1-keto-2-naphthyl]amino]benzoic acid	IC50	919 nM
3-[[(4E)-4-(4-ethylphenyl)sulfonylimino-1-keto-2-naphthyl]amino]benzoic acid	IC50	926 nM
1H-Benzo[a]carbazole-1,4(11H)-dione, 8-methoxy-11- methyl-	IC50	946 nM
4-[[(4E)-4-(4-ethylphenyl)sulfonylimino-1-keto-2-naphthyl]amino]benzoic acid	IC50	966 nM
4-({(4Z)-1-oxo-4-[(phenylsulfonyl)imino]-1,4-dihydronaphthalen-2-yl}amino)benzoic acid	IC50	967 nM
1-Decyloxycarbonylmethyl-3-methyl-2-o-tolyloxymethyl-3H-benzoimidazol-1-ium	EC50	1020 nM
(6E)-6-[[[2,6-bis(1-pyrrolidinyl)-4-pyrimidinyl]hydrazo]methylidene]-1-cyclohexa-2,4-dienone	IC50	1030 nM
2-[[2-[2-(dimethylamino)ethylamino]-1-oxoethyl]amino]-4-(4-phenylphenyl)-3-thiophenecarboxylic acid ethyl ester;hydrochloride	EC50	1090 nM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3-quinolin-2-ylpropanoyl]amino]-3-methylbutanoyl]amino]-5-phenoxysulfonylpent-4-enoic acid	IC50	1200 nM	US-9045524: Selective caspase inhibitors and uses thereof
MLS002471441	IC50	1220 nM
2-[5-[(Z)-(3-bromanyl-8-oxidanylidene-[1,3]thiazolo[4,5]imidazo[1,2-b]pyridin-7-ylidene)methyl]furan-2-yl]benzoic acid	IC50	1250 nM
4-[(E)-[3-(2-carbomethoxyanilino)-4-keto-1-naphthylidene]amino]sulfonylbenzoic acid	IC50	1260 nM
SMR000516584	IC50	1270 nM
(NE)-4-ethyl-N-[3-(4-hydroxyanilino)-4-keto-1-naphthylidene]benzenesulfonamide	IC50	1280 nM
(E,3S)-5-(benzenesulfonyl)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-(4-hydroxyphenyl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3-methylbutanoyl]amino]propanoyl]amino]pent-4-enoic acid	IC50	1300 nM	US-9045524: Selective caspase inhibitors and uses thereof
cid_738951	IC50	1380 nM
4-[(5E)-5-[[5-(1,3-benzothiazol-2-yl)-2-furanyl]methylidene]-4-oxo-2-sulfanylidene-3-thiazolidinyl]butanoic acid	IC50	1380 nM
(4S)-5-[[(2S)-1-[[(E,2S)-1-carboxy-4-methylsulfonylbut-3-en-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-5-oxopentanoic acid	IC50	1400 nM	US-9045524: Selective caspase inhibitors and uses thereof
1-ethyl-6-methyl-3-[(E)-2-phenylethenyl]pyrimido[5,4-e][1,2,4]triazine-5,7-dione	EC50	1440 nM
3-(4-fluorophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid	EC50	1450 nM
(5S)-4-[2-(3,4-dichlorophenyl)ethyl]-1-[(1R)-5-[methyl(p-anisyl)amino]-1-[(p-anisylamino)methyl]pentyl]-5-phenyl-piperazine-2,3-quinone	EC50	1480 nM
6-bromo-3-(2-methoxyanilino)-2H-isoquinolin-1-one	IC50	1510 nM
(8S)-7-(4-chlorobenzoyl)-3-(3-methacrylamidophenyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-8-carboxamide	IC50	1540 nM
MLS000686315	IC50	1610 nM
1,3,6-Trimethyl-1H-pyrimido[5,4-e][1,2,4]triazine-5,7-dione	EC50	1610 nM
4-[[(4E)-1-keto-4-mesitylsulfonylimino-2-naphthyl]amino]benzoic acid	IC50	1680 nM
1-Decyloxycarbonylmethyl-3-methyl-2-p-tolyloxymethyl-3H-benzoimidazol-1-ium	EC50	1800 nM
MLS000590906	IC50	1800 nM
cid_2851959	IC50	1840 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
3-phenyl-9,10-phenanthrenedione	IC50	2000 nM
(2R,3R)-1-N,3-dimethyl-2-N-[(2R)-3-naphthalen-1-yl-2-[2-[3-(trifluoromethyl)phenyl]ethylamino]propyl]pentane-1,2-diamine	EC50	2030 nM
6-(4-bromophenyl)-2-(methylsulfonyl)-4-phenylnicotinonitrile	IC50	2070 nM
cid_367783	IC50	2080 nM
4-piperidin-1-ylnaphthalene-1,2-dione	IC50	2120 nM

ChEMBL bioactivities

53 potent at pChembl≥5 of 82 total, top 47 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.70	IC50	2	nM	CHEMBL5715932
8.68	IC50	2.1	nM	CHEMBL5715925
8.30	IC50	5	nM	CHEMBL23226
8.22	IC50	6	nM	CHEMBL237310
8.05	IC50	9	nM	CHEMBL185356
7.80	EC50	16	nM	CHEMBL1091826
7.52	IC50	30	nM	CHEMBL180263
7.46	IC50	35	nM	CHEMBL5715934
7.42	IC50	38	nM	CHEMBL5792878
7.32	Ki	48	nM	CHEMBL5723323
7.31	IC50	49.2	nM	CHEMBL5715921
7.14	IC50	72.8	nM	CHEMBL5723349
6.97	IC50	107	nM	CHEMBL5822466
6.92	Ki	120	nM	CHEMBL439753
6.91	IC50	122	nM	CHEMBL6026985
6.80	IC50	160	nM	CHEMBL90224
6.67	AC50	214	nM	CHEMBL1325945
6.64	IC50	230	nM	CHEMBL90307
6.62	EC50	240	nM	CHEMBL4460352
6.62	IC50	240	nM	CHEMBL5715929
6.54	EC50	290	nM	CHEMBL2096803
6.52	IC50	300	nM	CHEMBL3673267
6.51	EC50	310	nM	CHEMBL4459769
6.50	AC50	317	nM	CHEMBL1463659
6.30	IC50	500	nM	CHEMBL3673265
6.30	IC50	500	nM	CHEMBL3673259
6.10	IC50	800	nM	CHEMBL2324339
6.07	Ki	850	nM	CHEMBL1907830
6.00	IC50	1000	nM	CHEMBL2324341
6.00	IC50	1000	nM	CHEMBL5752244
5.96	IC50	1100	nM	CHEMBL2323967
5.96	Ki	1100	nM	CHEMBL60190
5.92	IC50	1200	nM	CHEMBL3673259
5.92	Ki	1200	nM	CHEMBL62993
5.87	AC50	1340	nM	CHEMBL1210769
5.80	IC50	1600	nM	CHEMBL3678067
5.76	IC50	1740	nM	CHEMBL2324340
5.64	IC50	2300	nM	CHEMBL2323966
5.57	IC50	2720	nM	CHEMBL330535
5.55	IC50	2800	nM	CHEMBL3678074
5.52	AC50	3040	nM	CHEMBL1522941
5.52	IC50	3000	nM	CHEMBL4438921
5.30	IC50	5000	nM	CHEMBL3287898
5.30	IC50	5000	nM	GRASSYSTATIN A
5.30	Ki	5000	nM	CHEMBL60306
5.14	Ki	7200	nM	CHEMBL293622
5.00	AC50	1.009e+04	nM	CHEMBL1707033

PubChem BioAssay actives

37 with measured affinity, of 116 total; 31 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
5-fluoro-3-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-4-oxopentanoic acid	49729: Compound was evaluated for its inhibitory activity against the Caspase-9 enzyme	ic50	0.0050	uM
4-fluoro-2-[[2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]benzoyl]amino]-3-oxobutanoic acid	302018: Inhibition of human caspase 9	ic50	0.0060	uM
3-[[(2S)-2-[(2,4-dichlorophenyl)methoxycarbonylamino]-3-methylbutanoyl]amino]-5-fluoro-4-oxopentanoic acid	240705: Inhibition concentration required against caspase-9	ic50	0.0090	uM
N-(4-methoxyphenyl)-N-methyl-1,2,3-benzotriazin-4-amine	1393168: Activation of caspase cascade in human T47D cells using N-(Ac-DEVD)-N’-ethoxycarbonyl-R110 fluorogenic substrate incubated for 48 hrs by fluorescent plate reader based assay	ec50	0.0160	uM
5-fluoro-3-[[(2S)-3-methyl-2-(phenylcarbamoyloxy)butanoyl]amino]-4-oxopentanoic acid	240593: Inhibitory concentration against Caspase-9	ic50	0.0300	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	0.1200	uM
(3S)-3-[[(2S)-4-methyl-2-[[2-(naphthalen-1-ylamino)acetyl]amino]pentanoyl]amino]-4-oxobutanoic acid	49728: Binding affinity towards human Caspase-9	ic50	0.1600	uM
(3S)-3-[[(2S)-4-methyl-2-[[2-(naphthalen-1-ylamino)-2-oxoacetyl]amino]pentanoyl]amino]-4-oxobutanoic acid	49728: Binding affinity towards human Caspase-9	ic50	0.2300	uM
(2S,3R)-1-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-3-phenoxy-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide	1553567: Inhibition of N-terminal CARD domain of caspase 9 (unknown origin)	ec50	0.2400	uM
(2S)-1-[(2S)-3,3-dimethyl-2-[[(2S)-2-(methylamino)propanoyl]amino]butanoyl]-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide	1553567: Inhibition of N-terminal CARD domain of caspase 9 (unknown origin)	ec50	0.2900	uM
2-[4-(3-oxo-1H-isoindol-2-yl)phenyl]propanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.3000	uM
(2S)-1-[(2S)-2-cyclohexyl-2-[[(2S)-2-(methylamino)propanoyl]amino]acetyl]-N-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]pyrrolidine-2-carboxamide	1553567: Inhibition of N-terminal CARD domain of caspase 9 (unknown origin)	ec50	0.3100	uM
4-oxo-4-(4-phenylphenyl)butanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.7600	uM
(E,3S)-3-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-5-methylsulfonylpent-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	0.8000	uM
Ketorolac	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	0.8500	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	0.8500	uM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-2-phenylacetyl]amino]-3-methylbutanoyl]amino]-6-ethoxy-6-oxohex-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	1.0000	uM
(E,3S)-3-[[(2S)-1-[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-3,3-dimethylbutanoyl]azetidine-2-carbonyl]amino]-5-methylsulfonylpent-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	1.1000	uM
5-[(2S)-2-(methoxymethyl)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	1.1000	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	1.2000	uM
(E,3S)-3-[[(2S,3S)-2-[[(2S)-5-amino-2-[[(2S)-3-(1H-indol-3-yl)-2-(phenylmethoxycarbonylamino)propanoyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]amino]-5-methylsulfonylpent-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	1.7400	uM
2-(4-phenylphenyl)acetic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	1.8000	uM
2-(5-benzoylthiophen-2-yl)propanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	2.2000	uM
(E,3S)-3-[[(2S)-1-[(2R)-2-[(4-amino-3-chlorobenzoyl)amino]-3,3-dimethylbutanoyl]pyrrolidine-2-carbonyl]amino]-5-methylsulfonylpent-4-enoic acid	726061: Inhibition of caspase-9 (unknown origin)	ic50	2.3000	uM
(3S)-3-[[(2S)-4-methyl-2-[(2-naphthalen-1-yloxyacetyl)amino]pentanoyl]amino]-4-oxobutanoic acid	49728: Binding affinity towards human Caspase-9	ic50	2.7200	uM
N-[(E)-1,3-benzodioxol-5-ylmethylideneamino]-1-cyclopropyl-6-fluoro-4-oxo-7-piperazin-1-ylquinoline-3-carboxamide	1653209: Activation of caspase 9 in human SMMC7721 cells	ic50	3.0000	uM
2-[4-(2-methylpropyl)phenyl]propanoic acid	1802657: Caspase Catalytic Activity Assay from Article 10.1016/j.chembiol.2017.02.003: “Non-steroidal Anti-inflammatory Drugs Are Caspase Inhibitors.”	ic50	4.9000	uM
1-benzyl-5-nitroindole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	5.0000	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	448867: Inhibition of caspase 9 after 10 to 15 mins by fluorescence assay	ic50	5.0000	uM
2-[4-[4-[(2R)-4-[(2-ethylphenyl)carbamoyl]-2-methyl-2,3-dihydro-1,4-benzoxazin-7-yl]phenyl]cyclohexyl]acetic acid	1155020: Inhibition of CASP9 (unknown origin)	ic50	5.0000	uM
1-methyl-5-nitroindole-2,3-dione	1796419: Caspase Inhibition Assay from Article 10.1021/jm0100537: “Potent and selective nonpeptide inhibitors of caspases 3 and 7.”	ki	7.2000	uM

CTD chemical–gene interactions

1042 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases reaction, affects cotreatment, decreases reaction, increases activity, affects reaction (+3 more)	53
Doxorubicin	increases cleavage, affects reaction, increases expression, affects cotreatment, decreases response to substance (+9 more)	46
Cisplatin	affects cotreatment, increases expression, decreases expression, increases cleavage, increases response to substance (+4 more)	44
Quercetin	affects cotreatment, increases activity, increases abundance, increases reaction, decreases expression (+6 more)	41
Acetylcysteine	increases expression, affects cotreatment, decreases expression, increases response to substance, decreases reaction (+5 more)	40
Bortezomib	increases cleavage, affects cotreatment, decreases reaction, increases activity, increases expression (+4 more)	33
Resveratrol	increases cleavage, decreases reaction, increases activity, increases expression, increases reaction (+2 more)	31
Hydrogen Peroxide	affects cotreatment, increases cleavage, increases expression, decreases expression, increases reaction (+3 more)	18
Plant Extracts	decreases reaction, increases activity, decreases expression, increases expression, affects cotreatment (+1 more)	18
benzyloxycarbonyl-leucyl-glutamyl-histidyl-aspartic acid fluoromethyl ketone	affects reaction, increases activity, affects cotreatment, decreases response to substance, decreases reaction (+3 more)	17
Fluorouracil	affects cotreatment, affects expression, decreases reaction, increases cleavage, increases reaction (+4 more)	17
Paclitaxel	affects cotreatment, affects reaction, decreases activity, increases expression, affects response to substance (+6 more)	16
Curcumin	affects cotreatment, increases cleavage, increases expression, increases reaction, increases activity (+2 more)	13
bisphenol A	increases expression, decreases reaction, affects cotreatment, decreases expression, increases cleavage (+1 more)	12
sodium arsenite	affects reaction, increases abundance, increases cleavage, decreases expression, decreases reaction (+8 more)	11
hydroquinone	decreases expression, increases activity, increases cleavage, increases expression, decreases reaction	11
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases reaction, increases expression, increases reaction, affects reaction, increases cleavage (+3 more)	11
pyrazolanthrone	decreases reaction, increases cleavage, increases expression, increases activity, increases reaction	11
Paraquat	affects cotreatment, decreases reaction, increases expression, decreases expression, increases cleavage (+4 more)	11
3-methyladenine	affects cotreatment, increases expression, increases activity, decreases reaction, increases cleavage (+2 more)	10
Etoposide	affects expression, increases reaction, affects cotreatment, affects reaction, increases activity (+2 more)	10
Cadmium Chloride	increases reaction, increases abundance, decreases reaction, decreases expression, increases cleavage (+3 more)	10
Celecoxib	increases reaction, affects cotreatment, increases activity, decreases reaction, increases cleavage	9
Sorafenib	affects cotreatment, decreases reaction, increases cleavage, increases activity, increases reaction	9
Tretinoin	increases cleavage, increases reaction, increases expression, affects cotreatment, increases activity	9
Staurosporine	increases cleavage, affects response to substance, increases activity	9
Particulate Matter	decreases reaction, increases expression, decreases methylation, decreases expression, increases secretion (+5 more)	9
SB 203580	decreases reaction, increases cleavage, affects cotreatment, increases activity	8
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	increases reaction, decreases activity, affects reaction, decreases reaction, increases cleavage (+2 more)	8
pifithrin	increases reaction, decreases reaction, increases cleavage, increases activity, affects cotreatment	8

ChEMBL screening assays

65 unique, capped per target: 63 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1020511	Binding	Inhibition of caspase 9 assessed as ratio of rate constant k3 to Ki for enzyme	Synthesis and structure-activity relationships of oxamyl dipeptide caspase inhibitors developed for the treatment of liver disease. — Bioorg Med Chem Lett
CHEMBL5723108	Functional	Affinity Biochemical interaction: (enzymatic assay (fluorogenic substrate cleavage)) EUB0002190aAD CASP9	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

9 cell lines: 6 cancer cell line, 2 telomerase immortalized cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1A9	Abcam THP-1 CASP9 KO	Cancer cell line	Male
CVCL_C6VW	MSOD	Telomerase immortalized cell line	Female
CVCL_C6VX	MSOD-B	Telomerase immortalized cell line	Female
CVCL_D7LT	Ubigene A-549 CASP9 KO	Cancer cell line	Male
CVCL_D8II	Ubigene HCT 116 CASP9 KO	Cancer cell line	Male
CVCL_D9B3	Ubigene HEK293 CASP9 KO	Transformed cell line	Female
CVCL_D9ZI	Ubigene HeLa CASP9 KO	Cancer cell line	Female
CVCL_KT46	HeLa SilenciX Caspase 9	Cancer cell line	Female
CVCL_SH00	HAP1 CASP9 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)