CASP6

Summary

CASP6 (caspase 6, HGNC:1507) is a protein-coding gene on chromosome 4q25, encoding Caspase-6 (P55212). Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity.

This gene encodes a member of the cysteine-aspartic acid protease (caspase) family of enzymes. 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 acid residues to produce two subunits, large and small, that dimerize to form the active enzyme. This protein is processed by caspases 7, 8 and 10, and is thought to function as a downstream enzyme in the caspase activation cascade. Alternative splicing of this gene results in multiple transcript variants that encode different isoforms.

Source: NCBI Gene 839 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 59 total
• Druggable target: yes — 10 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001226

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1507
Approved symbol	CASP6
Name	caspase 6
Location	4q25
Locus type	gene with protein product
Status	Approved
Aliases	MCH2, caspase-6, CSP-6
Ensembl gene	ENSG00000138794
Ensembl biotype	protein_coding
OMIM	601532
Entrez	839

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 3 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000265164, ENST00000352981, ENST00000503684, ENST00000505117, ENST00000505486, ENST00000507550, ENST00000508203, ENST00000510324

RefSeq mRNA: 2 — MANE Select: NM_001226 NM_001226, NM_032992

CCDS: CCDS3684, CCDS3685

Canonical transcript exons

ENST00000265164 — 7 exons

Exon	Start	End
ENSE00000935047	109697622	109697768
ENSE00001018825	109703356	109703445
ENSE00001820381	109688628	109689568
ENSE00003504478	109690850	109691009
ENSE00003513525	109698300	109698342
ENSE00003596076	109696410	109696486
ENSE00003650192	109694525	109694700

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 96.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.5693 / max 71.5713, expressed in 1678 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53600	6.5693	1678

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
rectum	UBERON:0001052	96.27	gold quality
mucosa of transverse colon	UBERON:0004991	95.57	gold quality
oocyte	CL:0000023	95.50	gold quality
secondary oocyte	CL:0000655	94.72	gold quality
jejunal mucosa	UBERON:0000399	94.65	gold quality
duodenum	UBERON:0002114	92.59	gold quality
pancreatic ductal cell	CL:0002079	92.56	gold quality
colonic mucosa	UBERON:0000317	92.49	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.64	gold quality
buccal mucosa cell	CL:0002336	91.46	gold quality
transverse colon	UBERON:0001157	91.10	gold quality
islet of Langerhans	UBERON:0000006	89.16	gold quality
amniotic fluid	UBERON:0000173	89.02	gold quality
intestine	UBERON:0000160	88.65	gold quality
large intestine	UBERON:0000059	88.59	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.59	gold quality
ventricular zone	UBERON:0003053	88.58	gold quality
small intestine	UBERON:0002108	88.47	gold quality
colon	UBERON:0001155	88.45	gold quality
body of pancreas	UBERON:0001150	87.80	gold quality
colonic epithelium	UBERON:0000397	87.77	gold quality
cervix squamous epithelium	UBERON:0006922	87.72	silver quality
pancreas	UBERON:0001264	87.65	gold quality
right lobe of liver	UBERON:0001114	87.29	gold quality
ileal mucosa	UBERON:0000331	86.97	gold quality
palpebral conjunctiva	UBERON:0001812	86.83	gold quality
gall bladder	UBERON:0002110	86.34	gold quality
ganglionic eminence	UBERON:0004023	86.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.23	gold quality
germinal epithelium of ovary	UBERON:0001304	86.17	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.20
E-GEOD-110499	no	256.07

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, MAF, TP53

miRNA regulators (miRDB)

40 targeting CASP6, 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-5692A	100.00	74.40	6850
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-105-5P	99.54	69.24	2060
HSA-MIR-7853-5P	99.54	69.30	2055
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6728-3P	98.63	67.63	1534
HSA-MIR-5089-5P	98.45	66.06	1388

Literature-anchored findings (GeneRIF, showing 40)

• identified executioner caspase-6 as a transcriptional target of p53. The mechanism involves DNA binding by p53 to the third intron of the caspase-6 gene and transactivation. (PMID:12089322)
• Pro-CASP6 was the only proenzyme whose localization was limited to the cytosol in U937 cells during TPA-induced differentiation. (PMID:12145703)
• ARK5 negatively regulates procaspase-6 by phosphorylation at Ser257, leading to resistance to the FasL/Fas system. (PMID:15273717)
• induced and utilized by human Astrovirus Yuc8 to promote processing of the capsid precursor and dissemination of the viral particles in CAC0-2 cells. (PMID:15280469)
• programmed cell death was executed by caspase 6 in Streptococcus pneumoniae infected lung epithelium (PMID:15321985)
• CASP-6 cleaves the N terminus of tau in vitro at D13, a semicanonical and hitherto undescribed caspase cleavage site in tau. This suggests a role for caspase-6 & N-terminal truncation of tau during neurofibrillary tangle & Alzheimer’s disease progression. (PMID:15356202)
• caspase-2, -6 and -7 expression in gastric cancer cells is decreased compared to in normal gastric mucosal cells (PMID:15511269)
• caspase 6 cleaves periplakin at an unconventional recognition site, amino acid sequence TVAD (PMID:15654952)
• results show that Csp-1 is an upstream positive regulator of Csp-6-mediated cell death in primary human neurons; also results suggest that the activation of Csp-1 must be accompanied by an apoptotic insult to induce Csp-6-mediated cell death (PMID:16123779)
• results suggest that splitting of BL41-E95-A cells induces de novo synthesis of a protein involved in the activation of casp-6 and casp-8, which cleaves 5-LO. (PMID:16135563)
• caspase-6 and its cleavage of lamin A are critical in apoptotic signaling triggered by resveratrol in the colon carcinoma cells, which can be activated in the absence of Bax or p53 (PMID:16518869)
• data indicate that the CASP6 gene is occasionally mutated in gastric and colorectal carcinomas; also, the data suggest the possibility that deficiency of caspase-6 expression might contribute to the pathogenesis of gastric cancers (PMID:16948818)
• Caspase-6 was overexpressed in 52.9% of the 210 cases studied, showing predominantly cyoplasmic with some nuclear staining. (PMID:16977583)
• Active caspase-6 could be an early instigator of neuronal dysfunction. (PMID:17392160)
• The experiments revealed that N induces the intrinsic apoptotic pathway, resulting in processing of N at residues 400 and 403 by caspase-6 and/or caspase-3. (PMID:18155731)
• Resveratrol displays converse dose-related effects on fluorouracil-evoked colon cancer cell apoptosis: the role of CASP6 is reported. (PMID:18497562)
• Expression of caspase 6 and caspase 14 genes were different between normal skin of keloid-prone individuals and normal skin of keloid-resistant patients. (PMID:18762957)
• Caspase 6 cleaves cyclin B1 during mitotic catastrophe. Mitotic & apoptotic functions may be linked by caspase-dependent processing of mitotic activators. (PMID:18820706)
• Report co-localization of hyperphosphorylated tau and caspases 3/6 in the brainstem of Alzheimer’s disease patients. (PMID:18946722)
• During hypoxia in tube-forming endothelial cells, caspase-7 is responsible for chromatin condensation and nuclear fragmentation while caspase-6 is responsible for DNA ladder formation. (PMID:19022247)
• The crystal structure of caspase-6, a selective effector of axonal degeneration. (PMID:19694615)
• p53 activation enhances XIAP inhibition-induced cell death by promoting mitochondrial release of second mitochondria-derived activator of caspases (SMAC) and by inducing the expression of caspase-6. (PMID:19897582)
• Casp-6 is activated in familial forms of Alzheimer disease, as previously observed in sporadic forms. (PMID:19915487)
• results show that p97 is cleaved by Casp6 in Alzheimer’s disease and suggest p97 cleavage as an important mechanism for ubiquitin proteasome system impairment (PMID:20427671)
• Data showed that prostate cancer and PIN cells display higher expression of the proapoptotic proteins caspase-6 and BNIP3 than normal cells. (PMID:20437871)
• The NPM mutant specifically inhibits the activities of the cell-death proteases, caspase-6 and -8, through direct interaction with their cleaved, active forms, but not the immature procaspases. (PMID:20606168)
• These results imply that pro-Casp6b could negatively regulate pro-Casp6a activation in neurons and prevent Casp6a-mediated axonal degeneration. (PMID:20682790)
• a central and so far underappreciated role of caspase-8 dimerization/dissociation in avoiding unwanted cell death by lethal amplification of caspase responses via the caspase-8, -3, -6 loop. (PMID:20702410)
• CASP6 can be activated and regulated through intramolecular self-cleavage. (PMID:20890311)
• Intact IRAK-M is strongly expressed in resting alveolar macrophages but is cleaved in patients with pneumonia via neutrophil-mediated induction of CASP-6 activity. (PMID:21098228)
• These data suggest that caspase-6 undergoes a significant conformational change upon substrate binding, adopting a structure that is more like canonical caspases. (PMID:21111746)
• Data suggest that Casp4, Casp 6 and TNFSF10 are differentially expressed in potentially fertile and subfertile men and represent useful biomarkers for predicting male fertility in combination with P1 and P2. (PMID:21317160)
• New crystal form of apo-caspase-6 is presented in canonical conformation by identifying the previous apostructure as a hydrogen-ion concentration (pH)-inactivated form of caspase-6. (PMID:21621544)
• Caspase-6 cleaves human TERT at residues E129 and D637 as part of the apoptosis pathway in cultured cells. (PMID:21936563)
• Results showed the inhibition mechanism of CASP6 phosphorylation and laid the foundation for a new strategy of rational CASP6 drug design. (PMID:22433863)
• peptide binds at a tetramerization interface that is uniquely present in zymogen caspase-6, rather than binding into the active site, and acts via a new allosteric mechanism that promotes caspase tetramerization (PMID:22683611)
• Results demonstrate that in the absence of caspase 6 activity, intrinsic triggers of apoptosis induce the receptor-interacting-kinase-1-dependent production of pro-inflammatory cytokines. (PMID:22858542)
• binding of zinc at the exosite is the primary route of inhibition, potentially locking caspase-6 into the inactive helical conformation. (PMID:22891250)
• Caspase 6 activity in entorhinal cortex identifies aged individuals at risk for developing Alzheimer’s disease. (PMID:23402898)
• Significant associations have been found between CpG sites and patient sex, including DNA methylation in CASP6, a gene that may respond to estradiol treatment, and in HSD17B12, which encodes a sex steroid hormone. (PMID:24058506)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	casp6b.1	ENSDARG00000025608
danio_rerio	casp6b.2	ENSDARG00000070368
danio_rerio	casp6a	ENSDARG00000093405
mus_musculus	Casp6	ENSMUSG00000027997
rattus_norvegicus	Casp6	ENSRNOG00000052613
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), CASP9 (ENSG00000132906), CASP1 (ENSG00000137752), CASP5 (ENSG00000137757), CASP3 (ENSG00000164305), CASP7 (ENSG00000165806), PYDC1 (ENSG00000169900), CASP4 (ENSG00000196954), CARD16 (ENSG00000204397), CASP12 (ENSG00000204403), CARD18 (ENSG00000255501)

Protein

Protein identifiers

Caspase-6 — P55212 (reviewed: P55212)

Alternative names: Apoptotic protease Mch-2

All UniProt accessions (3): P55212, D6RBM3, D6RHU3

UniProt curated annotations — full annotation on UniProt →

Function. Cysteine protease that plays essential roles in programmed cell death, axonal degeneration, development and innate immunity. Acts as a non-canonical executioner caspase during apoptosis: localizes in the nucleus and cleaves the nuclear structural protein NUMA1 and lamin A/LMNA thereby inducing nuclear shrinkage and fragmentation. Lamin-A/LMNA cleavage is required for chromatin condensation and nuclear disassembly during apoptotic execution. Acts as a regulator of liver damage by promoting hepatocyte apoptosis: in absence of phosphorylation by AMP-activated protein kinase (AMPK), catalyzes cleavage of BID, leading to cytochrome c release, thereby participating in nonalcoholic steatohepatitis. Cleaves PARK7/DJ-1 in cells undergoing apoptosis. Involved in intrinsic apoptosis by mediating cleavage of RIPK1. Furthermore, cleaves many transcription factors such as NF-kappa-B and cAMP response element-binding protein/CREBBP. Cleaves phospholipid scramblase proteins XKR4 and XKR9. In addition to apoptosis, involved in different forms of programmed cell death. Plays an essential role in defense against viruses by acting as a central mediator of the ZBP1-mediated pyroptosis, apoptosis, and necroptosis (PANoptosis), independently of its cysteine protease activity. PANoptosis is a unique inflammatory programmed cell death, which provides a molecular scaffold that allows the interactions and activation of machinery required for inflammasome/pyroptosis, apoptosis and necroptosis. Mechanistically, interacts with RIPK3 and enhances the interaction between RIPK3 and ZBP1, leading to ZBP1-mediated inflammasome activation and cell death. Plays an essential role in axon degeneration during axon pruning which is the remodeling of axons during neurogenesis but not apoptosis. Regulates B-cell programs both during early development and after antigen stimulation. (Microbial infection) Proteolytically cleaves the N protein of coronaviruses such as MERS-CoV and SARS-CoV. The cleavage of MERS-CoV N-protein leads to two fragments and modulates coronavirus replication by regulating IFN signaling. The two fragments produced by the cleavage interact with IRF3 inhibiting its nuclear translocation after activation and reduce the expression of IFNB and IFN-stimulated genes. The same mechanism seems to be used by other coronaviruses such as SARS-CoV and SARS-CoV-2 to enhance their replication.

Subunit / interactions. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (p18) and a 11 kDa (p11) subunits. Interacts with BIRC6/bruce. Interacts with RIPK3. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit. Heterotetramer that consists of two anti-parallel arranged heterodimers, each one formed by a 18 kDa (Caspase-6 subunit p18) and a 11 kDa (Caspase-6 subunit p11) subunit.

Subcellular location. Cytoplasm. Nucleus.

Post-translational modifications. Phosphorylated by NUAK1; phosphorylation inhibits self-activation. Phosphorylation at Ser-257 by AMP-activated protein kinase (PRKAA1 or PRKAA2) inhibits autocleavage, preventing caspase activation, thereby preventing hepatocyte apoptosis. Palmitoylation by ZDHHC17 blocks dimerization and subsequent activation, leading to inhibit the cysteine protease activity. Can be cleaved and activated by different caspases, depending on the context. Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain. Cleaved and activated by CASP1, possibly in the context of inflammation.

Activity regulation. During activation, the N-terminal disordered prodomain is removed by cleavage. Concomitantly, double cleavage gives rise to a large 18-kDa and a small 11-kDa subunit. The two large and two small subunits then assemble to form the active CASP6 complex. Can be cleaved and activated by different caspases, depending on the context. Cleaved and activated by caspase-8 (CASP8) and subsequently by caspase-3 (CASP3). Can also undergo autoactivation by mediating autocleavage at Asp-179 and Asp-193, while it is not able to cleave its N-terminal disordered prodomain. Intramolecular cleavage at Asp-193 is a prerequisite for CASP6 self-activation. Cleaved and activated by CASP1 in neurons, possibly in the context of inflammation. Phosphorylation at Ser-257 inhibits autocleavage, preventing caspase activation. Specifically inhibited by compound 3 (benzyloxycarbonyl (Z)-VEID-tetrafluorophenoxymethyl ketone).

Domain organisation. The N-terminal disordered prodomain is required to prevent self-activation. The Tri-arginine exosite is required to recruit substrates for hydrolysis. Undergoes helix-strand structural transitions upon substrate-binding: the 130’s region interconverts between an inactive helical state and the canonically active strand state. Other caspases rest constitutively in the strand conformation before and after substrate-binding.

Similarity. Belongs to the peptidase C14A family.

Isoforms (2)

UniProt ID	Names	Canonical?
P55212-1	Alpha	yes
P55212-2	Beta

RefSeq proteins (2): NP_001217, NP_116787 (=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 3.4.22.59 — caspase-6 (BRENDA: 8 organisms, 159 substrates, 141 inhibitors, 28 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
AC-VAL-GLU-ILE-ASP-7-AMIDO-4-TRIFLUOROMETHYLCOUM	0.0227–0.315	7
N-ACETYL-VEID-7-AMIDO-4-METHYLCOUMARIN	0.082–0.176	5
N-ACETYL-VAL-GLU-ILE-ASP-7-AMIDO-4-METHYLCOUMARI	0.0134–0.0306	4
(N-ACETYL-VEID)2-RHODAMINE110	0.08	1
ACETYL-DEVD-4-NITROANILIDE	0.18	1
ACETYL-DQMD-4-NITROANILIDE	1.3	1
ACETYL-LEVD-4-NITROANILIDE	0.16	1
ACETYL-VDQQD-4-NITROANILIDE	7	1
ACETYL-VEHD-7-AMIDO-4-METHYLCOUMARIN	0.17	1
ACETYL-VEID-4-NITROANILIDE	0.03	1
ACETYL-VQVD-4-NITROANILIDE	0.58	1
ACETYL-YEVD-4-NITROANILIDE	1.2	1
N-ACETYL-ASP-GLU-VAL-ASP-7-AMIDO-4-METHYLCOUMARI	0.126	1
N-ACETYL-ASP-GLU-VAL-ASP-7-AMIDO-4-TRIFLUOROMETH	0.087	1
N-ACETYL-VAL-GLU-HIS-ASP-7-AMIDO-4-METHYLCOUMARI	0.246	1

UniProt features (59 total): strand 17, mutagenesis site 12, helix 8, turn 4, sequence variant 3, region of interest 3, propeptide 2, chain 2, modified residue 2, lipid moiety-binding region 2, active site 2, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

37 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3OD5	X-RAY DIFFRACTION	1.6
3S70	X-RAY DIFFRACTION	1.62
4N7J	X-RAY DIFFRACTION	1.67
4NBN	X-RAY DIFFRACTION	1.75
4NBL	X-RAY DIFFRACTION	1.76
8EG6	X-RAY DIFFRACTION	1.82
3P4U	X-RAY DIFFRACTION	1.9
4NBK	X-RAY DIFFRACTION	1.94
2WDP	X-RAY DIFFRACTION	1.95
4N5D	X-RAY DIFFRACTION	2.06
4HVA	X-RAY DIFFRACTION	2.07
4N7M	X-RAY DIFFRACTION	2.12
8EG5	X-RAY DIFFRACTION	2.14
4N6G	X-RAY DIFFRACTION	2.14
3V6L	X-RAY DIFFRACTION	2.2
8F97	X-RAY DIFFRACTION	2.32
6DEV	X-RAY DIFFRACTION	2.35
3P45	X-RAY DIFFRACTION	2.53
8F9A	X-RAY DIFFRACTION	2.55
4EJF	X-RAY DIFFRACTION	2.65
3QNW	X-RAY DIFFRACTION	2.65
8F78	X-RAY DIFFRACTION	2.65
8F9B	X-RAY DIFFRACTION	2.65
8F9D	X-RAY DIFFRACTION	2.65
3V6M	X-RAY DIFFRACTION	2.69
4IYR	X-RAY DIFFRACTION	2.7
8F98	X-RAY DIFFRACTION	2.7
6DEU	X-RAY DIFFRACTION	2.8
8F9C	X-RAY DIFFRACTION	2.8
4FXO	X-RAY DIFFRACTION	2.85

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55212-F1	85.54	0.67

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 (4): 257, 264, 277, 79

Mutagenesis-validated functional residues (12):

Position	Phenotype
23	abolished activation due to the presence of the n-terminal disordered prodomain. abolished processing and subsequent act
42–44	decreased ability to hydrolyze substrates.
121	catalytically inactive active-site mutant.
135	increased stability.
163	catalytically inactive active-site mutant.
179	abolished processing and subsequent activation; when associated with a-23 and a-193.
193	abolished processing and subsequent activation; when associated with a-23 and a-179.
257	abolished phosphorylation, leading to caspase-6 activation.
257	phospho-mimetic mutant; prevents caspase-6 autoactivation.
257	phospho-mimetic mutant; loss of self-activation.
264	reduced palmitoylation, leading to increased cysteine protease activity.
277	reduced palmitoylation, leading to increased cysteine protease activity.

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-111465	Apoptotic cleavage of cellular proteins
R-HSA-264870	Caspase-mediated cleavage of cytoskeletal proteins
R-HSA-352238	Breakdown of the nuclear lamina
R-HSA-6803207	TP53 Regulates Transcription of Caspase Activators and Caspases
R-HSA-109581	Apoptosis
R-HSA-212436	Generic Transcription Pathway
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5357801	Programmed Cell Death
R-HSA-5633008	TP53 Regulates Transcription of Cell Death Genes
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-75153	Apoptotic execution phase

MSigDB gene sets: 292 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, chr4q25, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, BROWNE_HCMV_INFECTION_6HR_DN, JI_RESPONSE_TO_FSH_UP, GOBP_INFLAMMATORY_RESPONSE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, LANG_MYB_FAMILY_TARGETS, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_MITOCHONDRIAL_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, MARTINEZ_RB1_TARGETS_UP, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION

GO Biological Process (15): activation of innate immune response (GO:0002218), proteolysis (GO:0006508), apoptotic process (GO:0006915), protein autoprocessing (GO:0016540), epithelial cell differentiation (GO:0030855), positive regulation of apoptotic process (GO:0043065), regulation of programmed cell death (GO:0043067), positive regulation of neuron apoptotic process (GO:0043525), positive regulation of necroptotic process (GO:0060545), pyroptotic inflammatory response (GO:0070269), intrinsic apoptotic signaling pathway by p53 class mediator (GO:0072332), cellular response to staurosporine (GO:0072734), hepatocyte apoptotic process (GO:0097284), protein maturation (GO:0051604), positive regulation of release of cytochrome c from mitochondria (GO:0090200)

GO Molecular Function (7): cysteine-type endopeptidase activity (GO:0004197), cysteine-type peptidase activity (GO:0008234), identical protein binding (GO:0042802), endopeptidase activity (GO:0004175), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Apoptotic cleavage of cellular proteins	2
Apoptotic execution phase	1
TP53 Regulates Transcription of Cell Death Genes	1
Programmed Cell Death	1
RNA Polymerase II Transcription	1
Generic Transcription Pathway	1
Transcriptional Regulation by TP53	1
Gene expression (Transcription)	1
Apoptosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein metabolic process	2
programmed cell death	2
peptidase activity	2
activation of immune response	1
positive regulation of innate immune response	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
protein processing	1
cell differentiation	1
epithelium development	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulation of cellular process	1
positive regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
regulation of necroptotic process	1
positive regulation of programmed necrotic cell death	1
necroptotic process	1
inflammatory response	1
signal transduction by p53 class mediator	1
intrinsic apoptotic signaling pathway	1
cellular response to alkaloid	1
response to staurosporine	1
epithelial cell apoptotic process	1
gene expression	1
release of cytochrome c from mitochondria	1
positive regulation of organelle organization	1
regulation of release of cytochrome c from mitochondria	1
endopeptidase activity	1
cysteine-type peptidase activity	1
protein binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

1590 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASP6	CASP8	Q14790	911
CASP6	TNFRSF21	O75509	865
CASP6	RIPK3	Q9Y572	860
CASP6	CASP1	P29466	834
CASP6	RIPK1	Q13546	790
CASP6	APP	P05067	767
CASP6	CYCS	P00001	736
CASP6	HTT	P42858	722
CASP6	DFFB	O76075	720
CASP6	APAF1	O14727	713
CASP6	DFFA	O00273	706
CASP6	BCL2	P10415	652
CASP6	BCL2L1	Q07817	632
CASP6	BAK1	Q16611	631
CASP6	FADD	Q13158	609

IntAct

686 interactions, top by confidence:

A	B	Type	Score
CASP6	CASP6	psi-mi:“MI:0915”(physical association)	0.870
CASP3	CASP6	psi-mi:“MI:0194”(cleavage reaction)	0.570
GCD7	CASP6	psi-mi:“MI:0915”(physical association)	0.560
CASP6	LNX1	psi-mi:“MI:0915”(physical association)	0.560
CASP6	NTAQ1	psi-mi:“MI:0915”(physical association)	0.560
CASP6	PKIA	psi-mi:“MI:0915”(physical association)	0.560
SERPINA3	CASP6	psi-mi:“MI:0915”(physical association)	0.560
CASP6	ANXA4	psi-mi:“MI:0915”(physical association)	0.560
CASP6	APOA4	psi-mi:“MI:0915”(physical association)	0.560
TRIM23	CASP6	psi-mi:“MI:0915”(physical association)	0.560
CASP6	ATF4	psi-mi:“MI:0915”(physical association)	0.560
CASP6	BAAT	psi-mi:“MI:0915”(physical association)	0.560
CASP6	BCAT1	psi-mi:“MI:0915”(physical association)	0.560
CASP6	BCHE	psi-mi:“MI:0915”(physical association)	0.560
CASP6		psi-mi:“MI:0915”(physical association)	0.560
CASP6	CAPN2	psi-mi:“MI:0915”(physical association)	0.560
CASP6	CAPN3	psi-mi:“MI:0915”(physical association)	0.560
CCNC	CASP6	psi-mi:“MI:0915”(physical association)	0.560
TEN1	CASP6	psi-mi:“MI:0915”(physical association)	0.560
CDKN2C	CASP6	psi-mi:“MI:0915”(physical association)	0.560
CASP6	CLTA	psi-mi:“MI:0915”(physical association)	0.560
CASP6	COL2A1	psi-mi:“MI:0915”(physical association)	0.560
CASP6	CRYBB3	psi-mi:“MI:0915”(physical association)	0.560
CASP6	CTNNB1	psi-mi:“MI:0915”(physical association)	0.560
CASP6	DLX3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (52): CASP6 (Two-hybrid), APP (Co-localization), CASP3 (Co-localization), CASP6 (Two-hybrid), CASP6 (Synthetic Lethality), MAPT (Biochemical Activity), MAPT (Biochemical Activity), N (Biochemical Activity), CHD3 (Two-hybrid), CASP6 (Two-hybrid), CASP6 (Two-hybrid), WDYHV1 (Two-hybrid), PKIA (Two-hybrid), CASP6 (Protein-peptide), CASP6 (Reconstituted Complex)

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

16 interactions.

A	Effect	B	Mechanism
CASP6	up-regulates	CASP8	cleavage
“Caspase 8 complex”	up-regulates	CASP6	cleavage
“Caspase 3 complex”	up-regulates	CASP6	cleavage
CASP8	up-regulates	CASP6	cleavage
CASP3	up-regulates	CASP6	cleavage
CASP6	down-regulates	LMNA	cleavage
NUAK1	“down-regulates activity”	CASP6	phosphorylation
CASP6	“form complex”	“Caspase 6 complex”	binding
CASP6	“up-regulates activity”	N	cleavage
CASP6	“up-regulates activity”	PSEN2	cleavage
CASP6	“up-regulates activity”	PSEN1	cleavage
CASP6	“up-regulates activity”	APP	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

970 predictions. Top by Δscore:

Variant	Effect	Δscore
4:109691005:CATGC:C	acceptor_gain	1.0000
4:109691010:CTACA:C	acceptor_loss	1.0000
4:109694519:TCTTA:T	donor_loss	1.0000
4:109694520:CTTAC:C	donor_loss	1.0000
4:109694521:TTACC:T	donor_loss	1.0000
4:109694522:TA:T	donor_loss	1.0000
4:109694523:A:AC	donor_gain	1.0000
4:109694523:A:AG	donor_loss	1.0000
4:109694524:C:CC	donor_gain	1.0000
4:109694696:TGACA:T	acceptor_gain	1.0000
4:109694697:GACA:G	acceptor_gain	1.0000
4:109694698:ACA:A	acceptor_gain	1.0000
4:109694699:CA:C	acceptor_gain	1.0000
4:109694699:CAC:C	acceptor_gain	1.0000
4:109694699:CACTA:C	acceptor_loss	1.0000
4:109694700:ACTA:A	acceptor_loss	1.0000
4:109694701:C:CA	acceptor_loss	1.0000
4:109694701:C:CC	acceptor_gain	1.0000
4:109694703:A:AC	acceptor_gain	1.0000
4:109694703:A:C	acceptor_gain	1.0000
4:109694713:C:CT	acceptor_gain	1.0000
4:109694713:C:T	acceptor_gain	1.0000
4:109694714:A:T	acceptor_gain	1.0000
4:109696408:AC:A	donor_gain	1.0000
4:109696409:CC:C	donor_gain	1.0000
4:109689565:TATC:T	acceptor_gain	0.9900
4:109689567:TC:T	acceptor_gain	0.9900
4:109689568:CC:C	acceptor_gain	0.9900
4:109689568:CCT:C	acceptor_loss	0.9900
4:109689569:C:CC	acceptor_gain	0.9900

AlphaMissense

1943 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:109690868:A:G	C209R	0.998
4:109694648:G:C	S120R	0.998
4:109694648:G:T	S120R	0.998
4:109694650:T:G	S120R	0.998
4:109697661:C:A	R64M	0.998
4:109689390:C:A	Q274H	0.997
4:109689390:C:G	Q274H	0.997
4:109689533:A:G	W227R	0.997
4:109689533:A:T	W227R	0.997
4:109689538:C:A	G225V	0.997
4:109689538:C:T	G225D	0.997
4:109689553:C:G	R220P	0.997
4:109690861:G:A	S211F	0.997
4:109694645:A:C	H121Q	0.997
4:109694645:A:T	H121Q	0.997
4:109694662:A:G	C116R	0.997
4:109697631:A:G	L74P	0.997
4:109697660:C:A	R64S	0.997
4:109697660:C:G	R64S	0.997
4:109697687:G:C	F55L	0.997
4:109697687:G:T	F55L	0.997
4:109697689:A:G	F55L	0.997
4:109689361:T:A	K284I	0.996
4:109689436:C:G	R259P	0.996
4:109689559:G:A	S218F	0.996
4:109690866:A:C	C209W	0.996
4:109690873:A:G	L207P	0.996
4:109690879:T:A	D205V	0.996
4:109694544:G:T	P155H	0.996
4:109697661:C:G	R64T	0.996

dbSNP variants (sampled 300 via entrez): RS1000027132 (4:109664868 T>C), RS1000067548 (4:109711432 T>A,C), RS1000137943 (4:109664535 C>G), RS1000196462 (4:109693448 G>A), RS1000265355 (4:109674579 A>G), RS1000311001 (4:109693825 G>A,C,T), RS1000372708 (4:109704650 G>A), RS1000377130 (4:109686780 G>T), RS1000389464 (4:109679537 T>G), RS1000493928 (4:109687950 A>G), RS1000495917 (4:109671041 T>G), RS1000648424 (4:109692180 C>T), RS1000747613 (4:109700657 C>T), RS1000796070 (4:109704459 G>A), RS1000827606 (4:109685264 C>T)

Disease associations

OMIM: gene MIM:601532 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007323_36	Risk-taking tendency (4-domain principal component model)	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3308 (SINGLE PROTEIN), CHEMBL3831289 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

10 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 174,783 (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
CHEMBL1200843	METHYLERGONOVINE MALEATE	4	1,139
CHEMBL1200885	ALOSETRON HYDROCHLORIDE	4	3,173
CHEMBL1200938	METHYSERGIDE MALEATE	4	4
CHEMBL1454910	NITROXOLINE	4	1,860
CHEMBL405110	METHYLENE BLUE ANHYDROUS	4	113,934
CHEMBL43128	PRIMAQUINE PHOSPHATE	4	2,032
CHEMBL459	METHYLDOPA	4	22,004
CHEMBL464982	GAMOLENIC ACID	3	26,552
CHEMBL508338	THIMEROSAL	3
CHEMBL98123	PAPAVERINE HYDROCHLORIDE	2	4,085

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — C14: Caspase

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

Ligand	Action	Affinity	Parameter
Ac-VEID-CHO	Inhibition	8.1	pIC50

Binding affinities (BindingDB)

35 measured of 75 human assays (75 total across all organisms); most potent 35 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
isatin Michael acceptor (IMA) analogue, 3	IC50	27.8 nM
(4S)-4-{[(1S)-1-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}-2-methylbutyl]carbamoyl}-4-[(2S)-2-acetamido-3-methylbutanamido]butanoic acid	IC50	60.5 nM
5-{[(4-{[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl}phenyl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	160 nM
4-oxo-4-(piperidin-1-yl)-N-(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-6-yl)butanamide	IC50	231 nM
2-oxo-1-phenyl-2-[(1,3,4-trioxo-1,2,3,4-tetrahydroisoquinolin-5-yl)amino]ethyl acetate	IC50	233 nM
3-Chloro-N-(1,2,3,4-tetrahydro-1,3,4-trioxoisoquinolin-6-yl)-propanamide	IC50	530 nM
N-(2-Methoxy-phenyl)-N-(1,3,4-trioxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-succinamide	IC50	537 nM
N-(1,3,4-Trioxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-succinamic acid	IC50	859 nM
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]pyridin-2-ylmethyl}sulfamoyl)-2-hydroxy-benzoic Acid	KI	1500 nM
Thiophene Scaffold 66a	KI	1900 nM
(E,3S)-3-[[(2S)-2-[[(2S)-2-[[(2S)-3-carboxy-2-(phenylmethoxycarbonylamino)propanoyl]amino]-2-phenylacetyl]amino]-3-methylbutanoyl]amino]-5-methylsulfonylpent-4-enoic acid	IC50	2000 nM	US-9045524: Selective caspase inhibitors and uses thereof
Heterocyclic deriv. 69b	KI	2700 nM
Thiophene Scaffold 66b	KI	3200 nM
isatin Michael acceptor (IMA) analogue, 18a	IC50	3300 nM
isatin Michael acceptor (IMA) analogue, 12a	IC50	3880 nM
Pyridine Scaffold 4	KI	3900 nM
isatin Michael acceptor (IMA) analogue, 11a	IC50	4100 nM
isatin Michael acceptor (IMA) analogue, 18b	IC50	4180 nM
isatin Michael acceptor (IMA) analogue, 13b	IC50	4300 nM
isatin Michael acceptor (IMA) analogue, 13a	IC50	4580 nM
isatin Michael acceptor (IMA) analogue, 19a	IC50	4700 nM
isatin Michael acceptor (IMA) analogue, 19b	IC50	4700 nM
isatin Michael acceptor (IMA) analogue, 12c	IC50	5350 nM
isatin Michael acceptor (IMA) analogue, 13c	IC50	5350 nM
N-(1,2,3,4-Tetrahydro-1,3,4-trioxoisoquinolin-7-yl)-4-nitrobenzamide	IC50	5670 nM
isatin Michael acceptor (IMA) analogue, 12b	IC50	6820 nM
(S)-5-({5-[1-Carboxymethyl-3-(2-chloro-benzylsulfanyl)-2-oxo-propylcarbamoyl]thiazol-2-hydroxy-benzoic Acidylmethyl}sulfamoyl)-2-	KI	8300 nM
5-(pyrrolidine-1-sulfonyl)-2,3-dihydro-1H-indole-2,3-dione	KI	9000 nM
1-methyl-5-nitro-2,3-dihydro-1H-indole-2,3-dione	KI	12000 nM
5-({(5-{[(2S)-1-carboxy-4-{[(2-chlorophenyl)methyl]sulfanyl}-3-oxobutan-2-yl]carbamoyl}thiophen-2-yl)methylamino}methyl)-2-hydroxybenzoic acid	KI	12000 nM
1-benzyl-5-nitro-2,3-dihydro-1H-indole-2,3-dione	KI	18000 nM
5-{[(2S)-2-[(phenylamino)methyl]pyrrolidine-1-]sulfonyl}-2,3-dihydro-1H-indole-2,3-dione	KI	21000 nM
5-{[(5-{[(2S)-1-carboxy-4-{[(2-chlorophenyl)methyl]sulfanyl}-3-oxobutan-2-yl]carbamoyl}pyrimidin-2-yl)methyl]sulfamoyl}-2-hydroxybenzoic acid	KI	25000 nM
2-[2-(4-Adamantan-1-yl-phenoxy)-acetylamino]-4-methyl-pentanoic acid (2-hydroxy-5-oxo-tetrahydro-furan-3-yl)-amide	IC50	32500 nM
1,2,3,4-tetrahydroisoquinoline-1,3,4-trione	IC50	50000 nM

ChEMBL bioactivities

459 potent at pChembl≥5 of 726 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.46	IC50	3.5	nM	CHEMBL101545
8.22	Ki	6	nM	CHEMBL3977587
8.20	Ki	6.3	nM	CHEMBL3917557
8.15	Ki	7	nM	CHEMBL382967
8.14	Ki	7.3	nM	CHEMBL3960740
8.13	Ki	7.4	nM	CHEMBL3927125
8.10	Ki	8	nM	CHEMBL315868
8.10	IC50	8	nM	CHEMBL478081
8.05	Ki	9	nM	CHEMBL91423
8.05	Ki	9	nM	CHEMBL371926
8.05	Ki	9	nM	CHEMBL3983217
8.05	IC50	8.9	nM	CHEMBL5715932
8.00	Ki	10	nM	CHEMBL3944828
8.00	IC50	10	nM	CHEMBL430648
8.00	IC50	10	nM	CHEMBL328412
7.96	Ki	11	nM	CHEMBL88795
7.96	Ki	11	nM	CHEMBL91281
7.96	Ki	11	nM	CHEMBL262735
7.96	Ki	11	nM	CHEMBL3961549
7.96	Ki	11	nM	CHEMBL3926784
7.96	Ki	11	nM	CHEMBL194207
7.92	Ki	12	nM	CHEMBL90185
7.92	IC50	12.12	nM	CHEMBL5563896
7.89	Ki	13	nM	CHEMBL197674
7.89	Ki	13	nM	CHEMBL330534
7.82	Ki	15	nM	CHEMBL199253
7.82	Ki	15	nM	CHEMBL372185
7.82	IC50	15	nM	CHEMBL100643
7.80	Ki	16	nM	CHEMBL88540
7.80	Ki	16	nM	CHEMBL3966591
7.80	EC50	16	nM	CHEMBL1091826
7.79	IC50	16.2	nM	CHEMBL5715932
7.77	Ki	17	nM	CHEMBL3934331
7.77	Ki	17	nM	CHEMBL1199647
7.75	AC50	18	nM	CHEMBL1563898
7.75	IC50	18	nM	CHEMBL23226
7.72	Ki	19	nM	CHEMBL3930460
7.72	Ki	19	nM	CHEMBL3909635
7.72	Ki	19	nM	CHEMBL3910303
7.72	Ki	19	nM	CHEMBL327821
7.70	Ki	20	nM	CHEMBL90268
7.70	Ki	20	nM	CHEMBL3928643
7.70	Ki	20	nM	CHEMBL314096
7.66	Ki	22	nM	CHEMBL3968852
7.66	Ki	22	nM	CHEMBL440211
7.66	Ki	22	nM	CHEMBL3950285
7.64	Ki	23	nM	CHEMBL3907290
7.60	Ki	25	nM	CHEMBL90914
7.60	Ki	25	nM	CHEMBL196266
7.60	Ki	25	nM	CHEMBL3914770

PubChem BioAssay actives

187 with measured affinity, of 739 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)-5-[[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-naphthalen-1-yloxy-5-oxopentanoic acid	49556: Inhibition of Caspase-6	ic50	0.0035	uM
(4S)-4-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-5-[[(2S,3S)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	415378: Inhibition of human recombinant caspase 6 assessed as accumulation of fluorogenic product by fluorometric assay	ic50	0.0080	uM
(4S)-4-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-5-[[(2S)-1-[[(2S)-1-carboxy-3-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.0080	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	49558: Inhibitory concentration of compound required against Caspase-6 enzyme compared to acylated dipeptides	ic50	0.0100	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	49557: Inhibitory concentration of compound required against Caspase-6 compared to acylated dipeptides	ic50	0.0100	uM
(4S)-4-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[(2-aminoacetyl)amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S,3R)-1-[[(2S)-1-[[(1S)-3-amino-1-carboxy-3-oxopropyl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	2098555: Inhibition of Caspase-6 activity (unknown origin) by FRET assay	ic50	0.0121	uM
(4R)-5-[[1-[[(3S)-2-hydroxy-5-oxooxolan-3-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-naphthalen-1-yloxy-5-oxopentanoic acid	49556: Inhibition of Caspase-6	ic50	0.0150	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-(phenylmethoxycarbonylamino)butanoyl]amino]-4-oxopentanoic acid	49547: Compound was evaluated for its inhibitory activity against the Caspase-6 enzyme	ic50	0.0180	uM
N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-[[2-(naphthalen-1-ylamino)acetyl]amino]pentanamide	49556: Inhibition of Caspase-6	ic50	0.0370	uM
(3S)-3-[[(2S)-4-methyl-2-[[2-(naphthalen-1-ylamino)acetyl]amino]pentanoyl]amino]-4-oxobutanoic acid	49546: Binding affinity towards human Caspase-6	ic50	0.0370	uM
5-fluoro-3-[[(2S)-3-methyl-2-(phenylcarbamoyloxy)butanoyl]amino]-4-oxopentanoic acid	240590: Inhibitory concentration against Caspase-6	ic50	0.0500	uM
4-fluoro-2-[[2-[[(2S)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]benzoyl]amino]-3-oxobutanoic acid	302015: Inhibition of human caspase 6	ic50	0.0610	uM
5-fluoro-2-[[[3-(1,2,4-triazin-3-yl)-2-pyridinyl]amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.0800	uM
5-[[5-[[(2S)-1-carboxy-4-(2-chlorophenyl)sulfanyl-3-oxobutan-2-yl]carbamoyl]-2-pyridinyl]methylsulfamoyl]-2-hydroxybenzoic acid	49549: Inhibitory activity against Caspase-6	ki	0.1200	uM
5-[[5-[[(2S)-1-carboxy-4-[(2-chlorophenyl)methylsulfanyl]-3-oxobutan-2-yl]carbamoyl]-2-pyridinyl]methylsulfamoyl]-2-hydroxybenzoic acid	1795219: Fluorometric Assay from Article 10.1021/jm020230j: “Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.”	ki	0.1200	uM
4-oxo-4-piperidin-1-yl-N-(1,3,4-trioxoisoquinolin-6-yl)butanamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.1240	uM
N’-(2-methoxyphenyl)-N-(1,3,4-trioxoisoquinolin-6-yl)butanediamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.1370	uM
2-(1-benzyl-2-oxo-5-thiomorpholin-4-ylsulfonylindol-3-ylidene)propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.1510	uM
2-[5-(azetidin-1-ylsulfonyl)-1-benzyl-2-oxoindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.1560	uM
5-fluoro-2-[[(3-pyrazin-2-yl-2-pyridinyl)amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.1800	uM
2-[1-[(4-methoxyphenyl)methyl]-2-oxo-5-thiomorpholin-4-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.1880	uM
5-[[5-[[(2S)-1-carboxy-4-[(2-chlorophenyl)methylsulfanyl]-3-oxobutan-2-yl]carbamoyl]pyrimidin-2-yl]methylsulfamoyl]-2-hydroxybenzoic acid	1795219: Fluorometric Assay from Article 10.1021/jm020230j: “Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.”	ki	0.1900	uM
2-[5-(azetidin-1-ylsulfonyl)-1-[(4-methoxyphenyl)methyl]-2-oxoindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.1970	uM
4-oxo-4-[(1,3,4-trioxoisoquinolin-6-yl)amino]butanoic acid	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.2010	uM
[2-oxo-1-phenyl-2-[(1,3,4-trioxoisoquinolin-5-yl)amino]ethyl] acetate	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.2160	uM
5-fluoro-2-[[[3-(1H-1,2,4-triazol-5-yl)-2-pyridinyl]amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.2200	uM
2-[1-[(3,4-dichlorophenyl)methyl]-2-oxo-5-thiomorpholin-4-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.2300	uM
2-(1-benzyl-2-oxo-5-pyrrolidin-1-ylsulfonylindol-3-ylidene)propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.2410	uM
5-fluoro-2-[[(3-pyrimidin-2-yl-2-pyridinyl)amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.2700	uM
2-[5-(azetidin-1-ylsulfonyl)-1-[(3,4-dichlorophenyl)methyl]-2-oxoindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.2800	uM
3-chloro-N-(1,3,4-trioxoisoquinolin-6-yl)propanamide	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.2830	uM
(2S)-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-(3-naphthalen-1-yloxypropanoylamino)pentanamide	49555: Inhibitory concentration required against caspase-6	ic50	0.3050	uM
N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-[[2-(3-phenoxyanilino)acetyl]amino]pentanamide	49556: Inhibition of Caspase-6	ic50	0.3080	uM
5-fluoro-2-[[[3-(1-methyltriazol-4-yl)-2-pyridinyl]amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.3100	uM
(2S)-N-[(3S)-2-hydroxy-5-oxooxolan-3-yl]-4-methyl-2-[2-(naphthalen-1-ylamino)propanoylamino]pentanamide	49556: Inhibition of Caspase-6	ic50	0.3100	uM
2-(1-benzyl-2-oxo-5-piperidin-1-ylsulfonylindol-3-ylidene)propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.3250	uM
2-[1-[(4-methoxyphenyl)methyl]-2-oxo-5-pyrrolidin-1-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.3580	uM
2-[2-oxo-5-[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl-1H-indol-3-ylidene]propanedinitrile	292077: Inhibition of human recombinant caspase 6	ic50	0.4070	uM
2-(1-benzyl-5-morpholin-4-ylsulfonyl-2-oxoindol-3-ylidene)propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.4250	uM
2-[1-[(4-methoxyphenyl)methyl]-2-oxo-5-[(2S)-2-(pyridin-3-yloxymethyl)azetidin-1-yl]sulfonylindol-3-ylidene]propanedinitrile	591189: Inhibition of caspase 6 by fluorometric assay	ic50	0.4500	uM
2-[1-[(4-methoxyphenyl)methyl]-5-morpholin-4-ylsulfonyl-2-oxoindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.4530	uM
2-[1-[(3,4-dichlorophenyl)methyl]-2-oxo-5-pyrrolidin-1-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.4680	uM
5-fluoro-2-[[(3-pyridazin-3-yl-2-pyridinyl)amino]methyl]phenol	1997371: Binding affinity at Caspase 6 (1 to 293) C163A mutant (unknown origin) expressed in Escherichia coli BL21-Gold (DE3) by SPR response measured	kd	0.4700	uM
isoquinoline-1,3,4-trione	1796413: Caspase Inhibition Assay from Article 10.1021/jm050896o: “Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors.”	ic50	0.4740	uM
2-[1-[[4-(2-fluoroethoxy)phenyl]methyl]-2-oxo-5-[(2S)-2-(pyridin-3-yloxymethyl)azetidin-1-yl]sulfonylindol-3-ylidene]propanedinitrile	591189: Inhibition of caspase 6 by fluorometric assay	ic50	0.5090	uM
2-[1-[(4-bromophenyl)methyl]-2-oxo-5-[(2S)-2-(pyridin-3-yloxymethyl)pyrrolidin-1-yl]sulfonylindol-3-ylidene]propanedinitrile	292077: Inhibition of human recombinant caspase 6	ic50	0.5150	uM
5-[[5-[[(2S)-1-carboxy-3-oxopropan-2-yl]carbamoyl]thiophen-2-yl]methylsulfamoyl]-2-hydroxybenzoic acid	1795219: Fluorometric Assay from Article 10.1021/jm020230j: “Identification of potent and selective small-molecule inhibitors of caspase-3 through the use of extended tethering and structure-based drug design.”	ki	0.5400	uM
2-[1-[(4-methoxyphenyl)methyl]-2-oxo-5-piperidin-1-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.5450	uM
2-[1-[(3,4-dichlorophenyl)methyl]-2-oxo-5-piperidin-1-ylsulfonylindol-3-ylidene]propanedinitrile	1799017: Enzyme Inhibition Assay from Article 10.1021/jm900135r: “Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6.”	ic50	0.5680	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	increases expression, affects reaction, increases activity, increases cleavage, increases reaction (+1 more)	4
Doxorubicin	affects activity, increases activity, increases expression, affects reaction	4
Estradiol	affects expression, decreases expression, decreases activity, increases degradation, decreases reaction	4
pyrazolanthrone	increases cleavage, increases activity, decreases reaction	3
Arsenic	affects cotreatment, decreases expression, increases expression	3
Mustard Gas	affects reaction, increases activity, increases cleavage, increases reaction	3
Quercetin	decreases expression, increases activity, increases expression	3
Tretinoin	decreases expression, affects cotreatment	3
Valproic Acid	decreases expression, increases expression	3
Cyclosporine	decreases expression	3
bisphenol A	decreases expression, affects cotreatment, increases expression	2
Bortezomib	increases cleavage, increases reaction	2
Acetylcysteine	decreases reaction, increases cleavage, increases activity	2
Air Pollutants	decreases expression, increases abundance	2
Aspirin	decreases reaction, increases activity, increases cleavage	2
Benzo(a)pyrene	affects methylation, increases expression	2
Cannabidiol	affects cotreatment, decreases expression	2
Deoxycholic Acid	affects response to substance, decreases reaction, increases activity	2
Drugs, Chinese Herbal	decreases expression, increases activity	2
Fluorouracil	affects expression, increases activity, increases cleavage, affects reaction	2
Hydrogen Peroxide	affects expression	2
Indomethacin	increases expression, affects reaction, increases activity, decreases reaction, increases reaction (+1 more)	2
Plant Extracts	affects cotreatment, increases expression, increases activity	2
Tobacco Smoke Pollution	increases expression	2
Cladribine	increases activity, increases reaction	2
Particulate Matter	increases abundance, decreases expression	2
7-hydroxydehydronuciferine	increases cleavage	1
moringin	affects cotreatment, decreases expression	1
dicrotophos	decreases expression	1
intybin	decreases expression	1

ChEMBL screening assays

86 unique, capped per target: 81 binding, 5 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1006644	Binding	Inhibition of human recombinant caspase 6 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
CHEMBL5723100	Functional	Affinity Biochemical interaction: (enzymatic assay (fluorogenic substrate cleavage)) EUB0002178aAD CASP6	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1VI	Abcam A-549 CASP6 KO	Cancer cell line	Male
CVCL_D2A4	Abcam HCT 116 CASP6 KO	Cancer cell line	Male
CVCL_D6AH	HyCyte A-549 KO-hCASP6	Cancer cell line	Male
CVCL_D9ZF	Ubigene HeLa CASP6 KO	Cancer cell line	Female
CVCL_SG94	HAP1 CASP6 (-) 1	Cancer cell line	Male
CVCL_SG95	HAP1 CASP6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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