Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVQTV1L)

• DOT Name: Caspase-4 (CASP4)
• Synonyms: CASP-4; EC 3.4.22.57; ICE and Ced-3 homolog 2; ICH-2; ICE(rel)-II; Mih1; Protease TX
• Gene Name: CASP4
• UniProt ID: CASP4_HUMAN
• PDB ID: 6KMZ; 6NRY; 7WR0; 7WR1; 7WR4; 7WR5; 7WR6; 8J6K; 8SPB
• EC Number: 3.4.22.57
• Pfam ID: PF00619 ; PF00656
• Sequence:
  MAEGNHRKKPLKVLESLGKDFLTGVLDNLVEQNVLNWKEEEKKKYYDAKTEDKVRVMADS
  MQEKQRMAGQMLLQTFFNIDQISPNKKAHPNMEAGPPESGESTDALKLCPHEEFLRLCKE
  RAEEIYPIKERNNRTRLALIICNTEFDHLPPRNGADFDITGMKELLEGLDYSVDVEENLT
  ARDMESALRAFATRPEHKSSDSTFLVLMSHGILEGICGTVHDEKKPDVLLYDTIFQIFNN
  RNCLSLKDKPKVIIVQACRGANRGELWVRDSPASLEVASSQSSENLEEDAVYKTHVEKDF
  IAFCSSTPHNVSWRDSTMGSIFITQLITCFQKYSWCCHLEEVFRKVQQSFETPRAKAQMP
  TIERLSMTRYFYLFPGN
• Function: Inflammatory caspase that acts as the effector of the non-canonical inflammasome by mediating lipopolysaccharide (LPS)-induced pyroptosis. Also indirectly activates the NLRP3 and NLRP6 inflammasomes. Acts as a thiol protease that cleaves a tetrapeptide after an Asp residue at position P1: catalyzes cleavage of CGAS, GSDMD and IL18. Effector of the non-canonical inflammasome independently of NLRP3 inflammasome and CASP1: the non-canonical inflammasome promotes pyroptosis through GSDMD cleavage without involving secretion of cytokine IL1B. In the non-canonical inflammasome, CASP4 is activated by direct binding to the lipid A moiety of LPS without the need of an upstream sensor. LPS-binding promotes CASP4 activation and CASP4-mediated cleavage of GSDMD and IL18, followed by IL18 secretion through the GSDMD pore, pyroptosis of infected cells and their extrusion into the gut lumen. Also indirectly promotes secretion of mature cytokines (IL1A and HMGB1) downstream of GSDMD-mediated pyroptosis via activation of the NLRP3 and NLRP6 inflammasomes. Involved in NLRP3-dependent CASP1 activation and IL1B secretion in response to non-canonical activators, such as UVB radiation or cholera enterotoxin. Involved in NLRP6 inflammasome-dependent activation in response to lipoteichoic acid (LTA), a cell-wall component of Gram-positive bacteria, which leads to CASP1 activation and IL1B secretion. Involved in LPS-induced IL6 secretion; this activity may not require caspase enzymatic activity. The non-canonical inflammasome is required for innate immunity to cytosolic, but not vacuolar, bacteria. Plays a crucial role in the restriction of S.typhimurium replication in colonic epithelial cells during infection. Pyroptosis limits bacterial replication, while cytokine secretion promotes the recruitment and activation of immune cells and triggers mucosal inflammation. May also act as an activator of adaptive immunity in dendritic cells, following activation by oxidized phospholipid 1-palmitoyl-2-arachidonoyl- sn-glycero-3-phosphorylcholine, an oxidized phospholipid (oxPAPC). Involved in cell death induced by endoplasmic reticulum stress and by treatment with cytotoxic APP peptides found in Alzheimer's patient brains. Cleavage of GSDMD is not strictly dependent on the consensus cleavage site but depends on an exosite interface on CASP4 that recognizes and binds the Gasdermin-D, C-terminal (GSDMD-CT) part. Catalyzes cleavage and maturation of IL18; IL18 processing also depends of the exosite interface on CASP4. In contrast, it does not directly process IL1B. During non-canonical inflammasome activation, cuts CGAS and may play a role in the regulation of antiviral innate immune activation ; (Microbial infection) In response to the Td92 surface protein of the periodontal pathogen T.denticola, activated by cathepsin CTSG which leads to production and secretion of IL1A and pyroptosis of gingival fibroblasts.
• Tissue Specificity: Widely expressed, including in keratinocytes and colonic and small intestinal epithelial cells (at protein level). Not detected in brain.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  NOD-like receptor sig.ling pathway (hsa04621)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
• Reactome Pathway:
  Pyroptosis (R-HSA-5620971)
  NOD1/2 Signaling Pathway (R-HSA-168638)
• BioCyc Pathway: MetaCyc:HS06388-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Caspase-4 (CASP4) increases the response to substance of Cisplatin.	[18]

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Caspase-4 (CASP4).	[1]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Caspase-4 (CASP4).	[35]

37 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Caspase-4 (CASP4).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Caspase-4 (CASP4).	[3]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Caspase-4 (CASP4).	[4]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Caspase-4 (CASP4).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Caspase-4 (CASP4).	[6]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Caspase-4 (CASP4).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Caspase-4 (CASP4).	[8]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Caspase-4 (CASP4).	[9]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Caspase-4 (CASP4).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Caspase-4 (CASP4).	[11]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Caspase-4 (CASP4).	[12]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Caspase-4 (CASP4).	[13]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Caspase-4 (CASP4).	[14]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the expression of Caspase-4 (CASP4).	[15]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Caspase-4 (CASP4).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Caspase-4 (CASP4).	[17]
Bortezomib	DMNO38U	Approved	Bortezomib increases the activity of Caspase-4 (CASP4).	[18]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Caspase-4 (CASP4).	[20]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Caspase-4 (CASP4).	[21]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Caspase-4 (CASP4).	[22]
Malathion	DMXZ84M	Approved	Malathion decreases the expression of Caspase-4 (CASP4).	[23]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Caspase-4 (CASP4).	[24]
Cocaine	DMSOX7I	Approved	Cocaine decreases the expression of Caspase-4 (CASP4).	[25]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the activity of Caspase-4 (CASP4).	[26]
Acocantherin	DM7JT24	Approved	Acocantherin increases the expression of Caspase-4 (CASP4).	[27]
Cantharidin	DMBP5N3	Approved	Cantharidin increases the expression of Caspase-4 (CASP4).	[29]
Riluzole	DMECBWN	Approved	Riluzole increases the activity of Caspase-4 (CASP4).	[30]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the activity of Caspase-4 (CASP4).	[31]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Caspase-4 (CASP4).	[32]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Caspase-4 (CASP4).	[33]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Caspase-4 (CASP4).	[34]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Caspase-4 (CASP4).	[36]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Caspase-4 (CASP4).	[37]
(E)-4-(3,5-dimethoxystyryl)phenol	DMYXI2V	Investigative	(E)-4-(3,5-dimethoxystyryl)phenol increases the activity of Caspase-4 (CASP4).	[38]
3,7,3',4'-TETRAHYDROXYFLAVONE	DMES906	Investigative	3,7,3',4'-TETRAHYDROXYFLAVONE increases the expression of Caspase-4 (CASP4).	[39]
Bafilomycin A1	DMUNK59	Investigative	Bafilomycin A1 increases the activity of Caspase-4 (CASP4).	[26]
GW7604	DMCA4RM	Investigative	GW7604 increases the expression of Caspase-4 (CASP4).	[15]

5 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroquinone	DM6AVR4	Approved	Hydroquinone increases the cleavage of Caspase-4 (CASP4).	[19]
Sertraline	DM0FB1J	Approved	Sertraline increases the cleavage of Caspase-4 (CASP4).	[28]
USNIC ACID	DMGOURX	Investigative	USNIC ACID increases the cleavage of Caspase-4 (CASP4).	[40]
CHLORANIL	DMCHGF1	Investigative	CHLORANIL increases the cleavage of Caspase-4 (CASP4).	[41]
ANTHRAQUINONE	DM29I0Y	Investigative	ANTHRAQUINONE increases the cleavage of Caspase-4 (CASP4).	[42]

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