CASP5

Summary

CASP5 (caspase 5, HGNC:1506) is a protein-coding gene on chromosome 11q22.3, encoding Caspase-5 (P51878). Thiol protease that acts as a mediator of programmed cell death.

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. Overexpression of the active form of this enzyme induces apoptosis in fibroblasts. Max, a central component of the Myc/Max/Mad transcription regulation network important for cell growth, differentiation, and apoptosis, is cleaved by this protein; this process requires Fas-mediated dephosphorylation of Max. The expression of this gene is regulated by interferon-gamma and lipopolysaccharide. Alternatively spliced transcript variants have been identified for this gene.

Source: NCBI Gene 838 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 82 total
• Druggable target: yes
• MANE Select transcript: NM_004347

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1506
Approved symbol	CASP5
Name	caspase 5
Location	11q22.3
Locus type	gene with protein product
Status	Approved
Aliases	ICE(rel)III
Ensembl gene	ENSG00000137757
Ensembl biotype	protein_coding
OMIM	602665
Entrez	838

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 14 protein_coding, 2 nonsense_mediated_decay

ENST00000260315, ENST00000393141, ENST00000418434, ENST00000438448, ENST00000444749, ENST00000456094, ENST00000456200, ENST00000526056, ENST00000531367, ENST00000861023, ENST00000861024, ENST00000861025, ENST00000861026, ENST00000861027, ENST00000958374, ENST00000958375

RefSeq mRNA: 4 — MANE Select: NM_004347 NM_001136109, NM_001136110, NM_001136112, NM_004347

CCDS: CCDS44718, CCDS44719, CCDS44720, CCDS8328

Canonical transcript exons

ENST00000260315 — 10 exons

Exon	Start	End
ENSE00001655407	105008807	105008980
ENSE00001785524	105007083	105007334
ENSE00001953807	104994243	104994347
ENSE00003500173	104997383	104997492
ENSE00003532730	105002028	105002201
ENSE00003542958	105000261	105000495
ENSE00003640757	104995740	104995842
ENSE00003666111	104998885	104999028
ENSE00003791091	105003274	105003383
ENSE00003847598	105023130	105023168

Expression profiles

Bgee: expression breadth ubiquitous, 152 present calls, max score 86.70.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.1314 / max 151.4889, expressed in 181 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122076	1.1314	181

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	86.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.32	silver quality
monocyte	CL:0000576	83.56	gold quality
mononuclear cell	CL:0000842	83.04	gold quality
leukocyte	CL:0000738	82.47	gold quality
blood	UBERON:0000178	82.28	gold quality
vermiform appendix	UBERON:0001154	82.11	gold quality
mucosa of transverse colon	UBERON:0004991	79.49	gold quality
colonic mucosa	UBERON:0000317	76.90	gold quality
transverse colon	UBERON:0001157	75.92	gold quality
caecum	UBERON:0001153	75.87	gold quality
small intestine Peyer’s patch	UBERON:0003454	75.45	gold quality
granulocyte	CL:0000094	74.85	gold quality
mucosa of sigmoid colon	UBERON:0004993	74.39	gold quality
small intestine	UBERON:0002108	73.51	gold quality
diaphragm	UBERON:0001103	73.39	gold quality
duodenum	UBERON:0002114	71.02	gold quality
spleen	UBERON:0002106	70.09	gold quality
jejunal mucosa	UBERON:0000399	69.09	gold quality
epithelium of nasopharynx	UBERON:0001951	69.00	gold quality
intestine	UBERON:0000160	68.54	gold quality
palpebral conjunctiva	UBERON:0001812	67.24	gold quality
pancreatic ductal cell	CL:0002079	67.02	silver quality
large intestine	UBERON:0000059	66.97	gold quality
colon	UBERON:0001155	66.25	gold quality
smooth muscle tissue	UBERON:0001135	66.15	gold quality
frontal pole	UBERON:0002795	65.77	gold quality
paraflocculus	UBERON:0005351	64.35	gold quality
germinal epithelium of ovary	UBERON:0001304	62.80	gold quality
vastus lateralis	UBERON:0001379	62.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting CASP5, 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-4492	99.87	68.25	3611
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-10525-3P	96.32	68.04	699

Literature-anchored findings (GeneRIF, showing 31)

• inflammasome comprises caspase-1, caspase-5, Pycard/Asc, and NALP1; a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta (PMID:12191486)
• Identification of caspase-5 coding region microsatellite mutations in vivo implicates this gene in the pathogenesis of human T-LBL/ALL (PMID:12479849)
• Caspase-5 might be a suppressor gene of highly metastatic potential in lung cancer (PMID:12964016)
• CASPASE-5, an acknowledged frameshift target in MSI+ gastrointestinal tract tumors, was frequently mutated in Microsatellite instability+ cell lines (PMID:15886296)
• novel exon was present in six alternatively spliced caspase-5 mRNA variants expressed in human peripheral blood mononuclear cells (PBMC) and encoded the previously unknown amino-terminus of caspase-5. (PMID:16893518)
• Alterations in TGF-betaRII, BAX, IGFIIR, caspase-5, hMSH3 and hMSH6 genes of microsatellite instability are rare in urinary bladder carcinoma and they are not associated with microsatellite instability or the presence of p53 mutations. (PMID:17676485)
• Caspase-5 gene is commonly mutated in the cancers with microsatellite instability suggesting that inactivation of caspase-5 may play a role in their tumorigenesis. (PMID:18430458)
• Coding polymorphisms in Casp5, Casp8 and DR4 genes may play a role in predisposition to lung cancer. (PMID:19203830)
• Single nucleotide polymorphisms in CASP5 and RBBP8 gene are associated with survival in ovarian cancer patients. (PMID:19270026)
• Unfavorable significance of CASP5 heterozygous genotype explained by its role in inflammation-related processes. (PMID:20434535)
• The changes of caspase-2 and caspase-5 activities could be indicative of their involvement in the cervical malignancy mechanisms. (PMID:21051981)
• Caspase-5 and the inflammasome may have an important role in the inflammatory response in psoriasis. (PMID:21191419)
• analysis of concerted antigen processing of a short viral antigen by human caspase-5 and -10 (PMID:21454616)
• Data suggest a positive association of caspase-3 and diplotype analysis of caspase-5 to be associated with prostate cancer risk. (PMID:21668377)
• Association of death receptor 4, Caspase 3 and 5 gene polymorphism with increased risk to bladder cancer in North Indians. (PMID:21700414)
• Mutual activation between caspase-5 and -1 suggests caspase-5 may work predominantly in concert with caspase-1 in modulating retinal pigment epithelium inflammatory responses. (PMID:21969293)
• Data show that exposure of hepatocytes to direct hypoxia resulted in acid sphingomyelinase activation and ceramide elevation associated with activation of caspase 5 and the subsequent cleavage of HuR and apoptotic cell death. (PMID:22906436)
• The distribution of the other genotypes; rs507879, rs518604 and rs523104 of caspase-5) was not significantly different between patients with psoriasis vulgaris and the healthy controls. (PMID:25753570)
• this study has identified epithelial-expressed caspases-4 and -5 as biomarkers with diagnostic and therapeutic potential in colorectal cancer. (PMID:25943872)
• both caspase-4 and caspase-5 are functionally important for appropriate responses to intracellular Gram-negative bacteria. (PMID:26173988)
• Caspase-4 and caspase-5 mediate IL-1alpha and IL-1beta release from human monocytes after lipopolysaccharides stimulation. (PMID:26508369)
• CASP5 gene overexpression significantly promoted angiogenesis ability of HMEC-1 cells, which was probably achieved by inhibiting angpt-1/Tie2 and promoting VEGF-1 signal pathway. (PMID:26884849)
• Th17 micro-milieu via IL-17A regulates NLRP1-dependent CASP5 activity in psoriatic skin autoinflammation. (PMID:28422993)
• Study shows that CASP5 was positively correlated with inflammation in rheumatoid arthritis (RA), and provides evidence that certain CASP5 SNPs were associated with an increased risk of RA. (PMID:29158166)
• Long non-coding RNA CASP5 promotes the malignant phenotypes of human glioblastoma multiforme. (PMID:29715460)
• Knockdown of caspase-4/5 preserved human tubular epithelial cells from cell death and reduced the release of mature IL-1beta. (PMID:30250284)
• The in vitro application of cyclic stretching induced programmed cell death by activation of caspase-3 and -5 in periodontal ligament cells, and these two caspases could interact with each other after mechanical stretch loading. (PMID:30604868)
• SNX10-mediated LPS sensing causes intestinal barrier dysfunction via a caspase-5-dependent signaling cascade. (PMID:34747049)
• CASP5 and CR1 as potential biomarkers for Kawasaki disease: an Integrated Bioinformatics-Experimental Study. (PMID:34895171)
• Inhibition of circular RNA circ_0138959 alleviates pyroptosis of human gingival fibroblasts via the microRNA-527/caspase-5 axis. (PMID:35030963)
• Caspase 5 depletion is linked to hyper-inflammatory response and progeroid syndrome. (PMID:37603195)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp8	ENSDARG00000058325
danio_rerio	casp3l	ENSDARG00000086266
danio_rerio	casp20	ENSDARG00000104367
danio_rerio		ENSDARG00000112575
drosophila_melanogaster	Dronc	FBGN0026404
drosophila_melanogaster	Decay	FBGN0028381
caenorhabditis_elegans		WBGENE00000417
caenorhabditis_elegans		WBGENE00000819
caenorhabditis_elegans		WBGENE00000820
caenorhabditis_elegans	csp-3	WBGENE00000821

Paralogs (16): CASP10 (ENSG00000003400), CFLAR (ENSG00000003402), CASP8 (ENSG00000064012), PYCARD (ENSG00000103490), CASP14 (ENSG00000105141), CASP2 (ENSG00000106144), CASP9 (ENSG00000132906), CASP1 (ENSG00000137752), CASP6 (ENSG00000138794), CASP3 (ENSG00000164305), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CASP4 (ENSG00000196954), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Protein

Protein identifiers

Caspase-5 — P51878 (reviewed: P51878)

Alternative names: ICE(rel)-III, Protease ICH-3, Protease TY

All UniProt accessions (3): P51878, C9JF14, H7C0P5

UniProt curated annotations — full annotation on UniProt →

Function. Thiol protease that acts as a mediator of programmed cell death. Initiates pyroptosis, a programmed lytic cell death pathway through cleavage of Gasdermin-D (GSDMD): cleavage releases the N-terminal gasdermin moiety (Gasdermin-D, N-terminal) that binds to membranes and forms pores, triggering pyroptosis. Also mediates cleavage and maturation of IL18. Cleavage of GSDMD and IL18 is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4. During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation.

Subunit / interactions. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 20 kDa (p20) and a 10 kDa (p10) subunits. Interacts with MEFV. Interacts with SERPINB1; this interaction regulates CASP5 activity.

Tissue specificity. Expressed in barely detectable amounts in most tissues except brain, highest levels being found in lung, liver and skeletal muscle.

Post-translational modifications. The two subunits are derived from the precursor sequence by an autocatalytic mechanism.

Induction. Up-regulated by bacterial lipopolysaccharides (LPS).

Miscellaneous. Most abundant isoform. Most abundant isoform. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay. Produced by alternative initiation at Met-71 of isoform 1.

Similarity. Belongs to the peptidase C14A family.

Isoforms (6)

UniProt ID	Names	Canonical?
P51878-1	1, caspase-5/a	yes
P51878-2	2, Caspase-5/b
P51878-3	3, Caspase-5/c
P51878-4	4, Caspase-5/e
P51878-5	5, Caspase-5/f
P51878-6	6, Caspase-5-S

RefSeq proteins (4): NP_001129581, NP_001129582, NP_001129584, NP_004338* (*=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

Pfam: PF00619, PF00656

Enzyme classification (BRENDA):

• EC 3.4.22.58 — caspase-5 (BRENDA: 2 organisms, 25 substrates, 17 inhibitors, 3 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ACETYL-WEHD-7-AMIDO-4-METHYLCOUMARIN	0.015	1
SUCCINYL-YVAD-7-AMIDO-4-METHYLCOUMARIN	0.86	1

UniProt features (27 total): sequence variant 11, splice variant 6, mutagenesis site 3, propeptide 2, chain 2, active site 2, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51878-F1	69.62	0.42

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): 267; 315

Mutagenesis-validated functional residues (3):

Position	Phenotype
315	abolishes protease activity.
324	abolished ability to cleave il18.
348–350	abolished ability to cleave il18.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-5620971	Pyroptosis
R-HSA-9948011	CASP5 inflammasome assembly
R-HSA-9960525	CASP5-mediated substrate cleavage
R-HSA-5218859	Regulated Necrosis
R-HSA-5357801	Programmed Cell Death

MSigDB gene sets: 111 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, chr11q22, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_PROTEIN_MATURATION, GOBP_NEURAL_NUCLEUS_DEVELOPMENT, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOBP_SUBSTANTIA_NIGRA_DEVELOPMENT, GOBP_MIDBRAIN_DEVELOPMENT, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEURON_APOPTOTIC_PROCESS, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOBP_HEAD_DEVELOPMENT, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS

GO Biological Process (9): proteolysis (GO:0006508), apoptotic process (GO:0006915), substantia nigra development (GO:0021762), positive regulation of neuron apoptotic process (GO:0043525), positive regulation of inflammatory response (GO:0050729), protein maturation (GO:0051604), cellular response to mechanical stimulus (GO:0071260), interleukin-18-mediated signaling pathway (GO:0035655), regulation of apoptotic process (GO:0042981)

GO Molecular Function (5): cysteine-type endopeptidase activity (GO:0004197), cysteine-type peptidase activity (GO:0008234), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), NLRP1 inflammasome complex (GO:0072558), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Non-canonical inflammasome activation	2
Regulated Necrosis	1
Programmed Cell Death	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
midbrain development	1
neural nucleus development	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
gene expression	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-18	1
apoptotic process	1
regulation of programmed cell death	1
endopeptidase activity	1
cysteine-type peptidase activity	1
peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
canonical inflammasome complex	1
cellular_component	1

Protein interactions and networks

STRING

1230 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP5	PYCARD	Q9ULZ3	998
CASP5	NLRP1	Q9C000	998
CASP5	CASP1	P29466	984
CASP5	NLRP3	Q96P20	924
CASP5	NLRC4	Q9NPP4	911
CASP5	CARD8	Q9Y2G2	900
CASP5	AIM2	O14862	884
CASP5	MEFV	O15553	863
CASP5	NLRP2	Q9NX02	863
CASP5	IL1B	P01584	811
CASP5	GSDMD	P57764	804
CASP5	IL18	Q14116	798
CASP5	NAIP	Q13075	731
CASP5	NLRP6	P59044	672
CASP5	PPHLN1	Q8NEY8	667

IntAct

7 interactions, top by confidence:

A	B	Type	Score
CASP5	CASP4	psi-mi:“MI:0914”(association)	0.530
CASP5	ARHGAP44	psi-mi:“MI:0914”(association)	0.530
NLRP1	CASP5	psi-mi:“MI:0915”(physical association)	0.400
Casp12	CASP5	psi-mi:“MI:0915”(physical association)	0.400
B4GAT1	CASP5	psi-mi:“MI:0915”(physical association)	0.400
CASP4	NME2P1	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): CASP4 (Affinity Capture-MS), ARHGAP44 (Affinity Capture-MS), LACRT (Affinity Capture-MS), PPHLN1 (Biochemical Activity), CASP5 (Synthetic Lethality), LACRT (Affinity Capture-MS), CASP5 (Affinity Capture-MS), ARHGAP44 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LIF8, B1ARD6, B1ARD8, G1SRW8, O08736, O14862, O35368, O89110, P0C7P3, P0DOV1, P13504, P29452, P41218, P43527, P51878, P55865, P55867, P70343, Q02955, Q075B4, Q08AF3, Q153Z0, Q16666, Q3UX83, Q4R7Q1, Q504J1, Q504N7, Q5RCZ8, Q5U311, Q60766, Q62929, Q6AYC2, Q6IEE8, Q6UXS9, Q7Z7L1, Q8BV49, Q8CGE8, Q8IXQ6, Q8IYM2, Q8SPH9

Diamond homologs: O08736, O35397, O75601, P29452, P29466, P42574, P43527, P49662, P51878, P55212, P55213, P55865, P55867, P70343, P70677, Q075B4, Q08DY9, Q153Z0, Q2PFV2, Q504J1, Q5E9C1, Q5IS54, Q5IS99, Q60431, Q6UXS9, Q8MJC3, Q8MJU1, Q8MKI5, Q920D5, Q95ND5, Q9I9L7, Q9MZV6, Q9MZV7, Q9N2I1, Q9TV13, F1NV61, Q5EG05, A0A1D5PPP7, O89094, P42573

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CASP5	“up-regulates activity”	GSDMD	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	11
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1638 predictions. Top by Δscore:

Variant	Effect	Δscore
11:104995734:ACTT:A	donor_loss	1.0000
11:104995736:TTA:T	donor_loss	1.0000
11:104995737:TA:T	donor_loss	1.0000
11:104995738:A:AC	donor_gain	1.0000
11:104995738:AC:A	donor_loss	1.0000
11:104995739:C:CA	donor_gain	1.0000
11:104995739:CA:C	donor_gain	1.0000
11:104995739:CAT:C	donor_gain	1.0000
11:104995739:CATT:C	donor_gain	1.0000
11:104995739:CATTT:C	donor_gain	1.0000
11:104995838:TGTAC:T	acceptor_gain	1.0000
11:104995840:TAC:T	acceptor_gain	1.0000
11:104995841:AC:A	acceptor_gain	1.0000
11:104995842:CC:C	acceptor_gain	1.0000
11:104995843:C:CC	acceptor_gain	1.0000
11:105002022:TCTTA:T	donor_loss	1.0000
11:105002023:CTTAC:C	donor_loss	1.0000
11:105002024:TTACC:T	donor_loss	1.0000
11:105002025:TA:T	donor_loss	1.0000
11:105002026:A:AC	donor_gain	1.0000
11:105002026:AC:A	donor_gain	1.0000
11:105002026:ACCCT:A	donor_loss	1.0000
11:105002027:C:CC	donor_gain	1.0000
11:105002027:C:T	donor_loss	1.0000
11:105002027:CC:C	donor_gain	1.0000
11:105002197:TAGAT:T	acceptor_gain	1.0000
11:105002198:AGAT:A	acceptor_gain	1.0000
11:105002199:GAT:G	acceptor_gain	1.0000
11:105002200:ATCT:A	acceptor_loss	1.0000
11:105002202:C:A	acceptor_loss	1.0000

AlphaMissense

2897 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:105002136:A:C	F203L	0.991
11:105002136:A:T	F203L	0.991
11:105002138:A:G	F203L	0.991
11:105000436:G:C	S259R	0.990
11:105000436:G:T	S259R	0.990
11:105000438:T:G	S259R	0.990
11:105000469:A:C	F248L	0.984
11:105000469:A:T	F248L	0.984
11:105000471:A:G	F248L	0.984
11:105000289:C:A	K308N	0.980
11:105000289:C:G	K308N	0.980
11:104995828:A:C	F407L	0.976
11:104995828:A:T	F407L	0.976
11:104995830:A:G	F407L	0.976
11:105000337:G:C	F292L	0.975
11:105000337:G:T	F292L	0.975
11:105000339:A:G	F292L	0.975
11:105000293:G:T	P307H	0.972
11:105000295:T:A	K306N	0.971
11:105000295:T:G	K306N	0.971
11:105000294:G:A	P307S	0.969
11:104995799:G:T	P417H	0.968
11:104995756:A:C	F431L	0.964
11:104995756:A:T	F431L	0.964
11:104995758:A:G	F431L	0.964
11:104997441:A:G	L383P	0.964
11:104995787:C:G	R421P	0.963
11:104998915:C:G	D356H	0.960
11:105000430:G:C	F261L	0.960
11:105000430:G:T	F261L	0.960

dbSNP variants (sampled 300 via entrez): RS1000142979 (11:104997655 C>G,T), RS1000144673 (11:105001060 C>G,T), RS1000216970 (11:105015955 G>C), RS1000235164 (11:105003734 T>A,C), RS1000278217 (11:105021438 A>G), RS1000293569 (11:105010029 C>T), RS1000615839 (11:105020412 T>A,C), RS1000631193 (11:105023349 A>G), RS1001044109 (11:105019982 G>A,C), RS1001255041 (11:104995558 T>C), RS1001277517 (11:105022627 A>G), RS1001361420 (11:105014298 T>A), RS1001422479 (11:105017071 C>T), RS1001623525 (11:105016766 C>A,G), RS1001707160 (11:105022333 GA>G,GAA)

Disease associations

OMIM: gene MIM:602665 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3131 (SINGLE PROTEIN), CHEMBL3831289 (PROTEIN FAMILY)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs554344	CASP5		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C14: Caspase

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
M826	Inhibition	6.7	pIC50
uracil 20	Inhibition	5.53	pIC50

Binding affinities (BindingDB)

17 measured of 47 human assays (47 total across all organisms); most potent 17 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-{[(4-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}phenyl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	160 nM
Z-Asp-(D,L Ala(2’-quinolyl))-Val- Aspphenyl vinylsulfone	IC50	300 nM	US-10167313: Selective caspase inhibitors and uses thereof
(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
(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
(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
(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
(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
(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
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]pyridin-2-ylmethyl}sulfamoyl)-2-hydroxy-benzoic Acid	KI	1500 nM
Thiophene Scaffold 66a	KI	1900 nM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-2-phenylacetyl]amino]-3-methylbutanoyl]amino]-5-methylsulfonylpent-4-enoic acid	IC50	2000 nM	US-9045524: Selective caspase inhibitors and uses thereof
Heterocyclic deriv. 69b	KI	2700 nM
Thiophene Scaffold 66b	KI	3200 nM
Pyridine Scaffold 4	KI	3900 nM
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]thiazol-2-hydroxy-benzoic Acidylmethyl}sulfamoyl)-2-	KI	8300 nM
5-({(5-{[(2S)-1-carboxy-4-{[(2-chlorophenyl)methyl]sulfanyl}-3-oxobutan-2-yl]carbamoyl}thiophen-2-yl)methylamino}methyl)-2-hydroxybenzoic acid	KI	12000 nM
5-{[(5-{[(2S)-1-carboxy-4-{[(2-chlorophenyl)methyl]sulfanyl}-3-oxobutan-2-yl]carbamoyl}pyrimidin-2-yl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	25000 nM

ChEMBL bioactivities

45 potent at pChembl≥5 of 57 total, top 43 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.80	Ki	16	nM	CHEMBL3949842
7.80	EC50	16	nM	CHEMBL1091826
7.67	IC50	21.3	nM	CHEMBL5715921
7.62	Ki	24	nM	CHEMBL3904435
7.55	Ki	28	nM	CHEMBL3970645
7.47	Ki	34	nM	CHEMBL3965572
7.47	Ki	34	nM	CHEMBL3941088
7.39	Ki	41	nM	CHEMBL3932441
7.33	Ki	47	nM	CHEMBL3905486
7.32	Ki	48	nM	CHEMBL3898411
7.23	Ki	59	nM	CHEMBL3895496
7.23	Ki	59	nM	CHEMBL3978901
7.15	IC50	71	nM	CHEMBL3949842
7.09	Ki	81	nM	CHEMBL3898379
7.00	Ki	99	nM	CHEMBL3984293
6.98	IC50	105	nM	CHEMBL3904435
6.96	Ki	111	nM	CHEMBL3939229
6.91	IC50	123	nM	CHEMBL3970645
6.87	Ki	135	nM	CHEMBL3968765
6.85	IC50	140	nM	CHEMBL5715925
6.84	IC50	146	nM	CHEMBL3965572
6.83	IC50	149	nM	CHEMBL3941088
6.81	IC50	155	nM	CHEMBL3895496
6.75	IC50	178	nM	CHEMBL3932441
6.70	IC50	200	nM	CHEMBL366927
6.69	IC50	205	nM	CHEMBL3905486
6.68	Ki	210	nM	CHEMBL1412861
6.68	IC50	210	nM	CHEMBL3898411
6.59	IC50	254	nM	CHEMBL3895496
6.59	IC50	254	nM	CHEMBL3978901
6.48	IC50	329	nM	CHEMBL5715924
6.47	IC50	340	nM	CHEMBL5715929
6.46	IC50	350	nM	CHEMBL3898379
6.37	IC50	430	nM	CHEMBL3984293
6.32	IC50	482	nM	CHEMBL3939229
6.25	IC50	560	nM	CHEMBL2323966
6.23	IC50	586	nM	CHEMBL3968765
6.12	IC50	750	nM	CHEMBL2324340
6.09	IC50	810	nM	CHEMBL179503
6.04	IC50	910	nM	CHEMBL1412861
5.59	IC50	2560	nM	CHEMBL3895496
5.53	IC50	2980	nM	CHEMBL4211859
5.30	IC50	5000	nM	GRASSYSTATIN A

PubChem BioAssay actives

45 with measured affinity, of 100 total; 28 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(4-methoxyphenyl)-N-methyl-1,2,3-benzotriazin-4-amine	1393168: Activation of caspase cascade in human T47D cells using N-(Ac-DEVD)-N’-ethoxycarbonyl-R110 fluorogenic substrate incubated for 48 hrs by fluorescent plate reader based assay	ec50	0.0160	uM
4-[4-(2-phenylethyl)piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0160	uM
4-[4-[(2-nitrophenyl)methyl]piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0240	uM
[4-[[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]methyl]phenyl]-phenylmethanone	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0280	uM
4-[4-[(3,5-dimethoxyphenyl)methyl]piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0340	uM
4-[4-(pyridin-4-ylmethyl)piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0340	uM
4-(4-benzylpiperazin-1-yl)-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0410	uM
4-piperazin-1-yl-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0470	uM
4-[4-[[3,5-bis(trifluoromethyl)phenyl]methyl]piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0480	uM
4-[4-(pyridin-3-ylmethyl)piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0590	uM
4-[4-(cyclohexylmethyl)piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0590	uM
3-[[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]methyl]-2,5,7,8-tetramethyl-3,4-dihydro-2H-chromen-6-ol	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0810	uM
4-[4-[(4-nitrophenyl)methyl]piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.0990	uM
4-[4-[(3-methoxyphenyl)methyl]piperazin-1-yl]-2,6-dipyrrolidin-1-ylpyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.1110	uM
2,4-dipyrrolidin-1-yl-6-[4-[[4-(trifluoromethyl)phenyl]methyl]piperazin-1-yl]pyrimidine	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.1350	uM
3-[2-[5-tert-butyl-3-[(4-methyl-1,2,5-oxadiazol-3-yl)methylamino]-2-oxopyrazin-1-yl]butanoylamino]-5-[hexyl(methyl)amino]-4-oxopentanoic acid;hydrochloride	241194: Inhibitory concentration against human caspase-5 in neuronal precursor (NT2) cells	ic50	0.2000	uM
(8S,10S,13S,14S,17S)-17-[2-[4-(2,6-dipyrrolidin-1-ylpyrimidin-4-yl)piperazin-1-yl]acetyl]-10,13-dimethyl-6,7,8,12,14,15,16,17-octahydrocyclopenta[a]phenanthren-3-one	1325504: Inhibition of human recombinant DTT-activated caspase-5 expressed in Escherichia coli using Ac-WEHD-AMC as substrate preincubated for 30 mins followed by substrate addition by fluorescence assay	ki	0.2100	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	0.4700	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	726064: Inhibition of caspase-5 (unknown origin)	ic50	0.5600	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	0.5900	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	726064: Inhibition of caspase-5 (unknown origin)	ic50	0.7500	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	241868: Inhibitory concentration against casp-5 in neuronal precursor (NT2) cells	ic50	0.8100	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	0.8700	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	1.0000	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	2.6000	uM
N-[3-[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]carbamoyl]cyclopropyl]-2,4-dioxo-1-propan-2-ylpyrimidin-5-yl]-2-methyl-4-(naphthalen-2-ylamino)benzamide	1369581: Inhibition of human recombinant caspase-5 using AC-WEHD-AMC as substrate at Km after 20 mins by fluorescence assay	ic50	2.9800	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	448863: Inhibition of caspase 5 after 10 to 15 mins by fluorescence assay	ic50	5.0000	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	8.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Paclitaxel	affects cotreatment, increases expression	3
Zoledronic Acid	affects expression, increases expression	2
Estradiol	affects expression	2
tetrachlorobenzoquinone	increases cleavage	1
9-hydroxyoctadecadienoic acid	increases expression	1
triphenyl phosphate	affects expression	1
sanguinarine	affects cotreatment, increases expression	1
bisphenol A	affects expression	1
VX-agent	increases expression	1
sodium arsenite	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
usnic acid	increases expression	1
SRT2183	increases expression	1
Arsenic Trioxide	increases expression, affects cotreatment	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Menthol	decreases expression	1
Metformin	affects cotreatment, increases expression	1
Paraquat	decreases expression	1
Rotenone	increases expression, increases reaction	1
Silicon Dioxide	decreases expression	1
Zidovudine	increases expression, affects cotreatment	1
Gold Compounds	affects cotreatment, increases expression	1
Lithium Chloride	increases expression	1
Cadmium Chloride	decreases expression	1
Lamivudine	affects cotreatment, increases expression	1
Copper Sulfate	increases expression	1
Nanotubes, Carbon	increases expression	1

ChEMBL screening assays

34 unique, capped per target: 32 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1039234	Binding	Inhibition of caspase 5 after 10 to 15 mins by fluorescence assay	Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation. — J Med Chem
CHEMBL5723097	Functional	Affinity Biochemical interaction: (enzymatic assay (fluorogenic substrate cleavage)) EUB0002176a CASP5	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Clinical trials (associated diseases)

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