Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTAPJ040)

• DOT Name: Caspase-7 (CASP7)
• Synonyms: CASP-7; EC 3.4.22.60; Apoptotic protease Mch-3; CMH-1; ICE-like apoptotic protease 3; ICE-LAP3
• Gene Name: CASP7
• UniProt ID: CASP7_HUMAN
• PDB ID: 1F1J ; 1GQF ; 1I4O ; 1I51 ; 1K86 ; 1K88 ; 1KMC ; 1SHJ ; 1SHL ; 2QL5 ; 2QL7 ; 2QL9 ; 2QLB ; 2QLF ; 2QLJ ; 3EDR ; 3H1P ; 3IBC ; 3IBF ; 3R5K ; 4FDL ; 4FEA ; 4HQ0 ; 4HQR ; 4JB8 ; 4JJ8 ; 4JR1 ; 4JR2 ; 4LSZ ; 4ZVO ; 4ZVP ; 4ZVQ ; 4ZVR ; 4ZVS ; 4ZVT ; 4ZVU ; 5IC6 ; 5K20 ; 5V6U ; 5V6Z ; 7WZS ; 8DGZ ; 8DJ3
• EC Number: 3.4.22.60
• Pfam ID: PF00656
• Sequence:
  MADDQGCIEEQGVEDSANEDSVDAKPDRSSFVPSLFSKKKKNVTMRSIKTTRDRVPTYQY
  NMNFEKLGKCIIINNKNFDKVTGMGVRNGTDKDAEALFKCFRSLGFDVIVYNDCSCAKMQ
  DLLKKASEEDHTNAACFACILLSHGEENVIYGKDGVTPIKDLTAHFRGDRCKTLLEKPKL
  FFIQACRGTELDDGIQADSGPINDTDANPRYKIPVEADFLFAYSTVPGYYSWRSPGRGSW
  FVQALCSILEEHGKDLEIMQILTRVNDRVARHFESQSDDPHFHEKKQIPCVVSMLTKELY
  FSQ
• Function: Thiol protease involved in different programmed cell death processes, such as apoptosis, pyroptosis or granzyme-mediated programmed cell death, by proteolytically cleaving target proteins. Has a marked preference for Asp-Glu-Val-Asp (DEVD) consensus sequences, with some plasticity for alternate non-canonical sequences. Its involvement in the different programmed cell death processes is probably determined by upstream proteases that activate CASP7. Acts as an effector caspase involved in the execution phase of apoptosis: following cleavage and activation by initiator caspases (CASP8, CASP9 and/or CASP10), mediates execution of apoptosis by catalyzing cleavage of proteins, such as CLSPN, PARP1, PTGES3 and YY1. Compared to CASP3, acts as a minor executioner caspase and cleaves a limited set of target proteins. Acts as a key regulator of the inflammatory response in response to bacterial infection by catalyzing cleavage and activation of the sphingomyelin phosphodiesterase SMPD1 in the extracellular milieu, thereby promoting membrane repair. Regulates pyroptosis in intestinal epithelial cells: cleaved and activated by CASP1 in response to S.typhimurium infection, promoting its secretion to the extracellular milieu, where it catalyzes activation of SMPD1, generating ceramides that repair membranes and counteract the action of gasdermin-D (GSDMD) pores. Regulates granzyme-mediated programmed cell death in hepatocytes: cleaved and activated by granzyme B (GZMB) in response to bacterial infection, promoting its secretion to the extracellular milieu, where it catalyzes activation of SMPD1, generating ceramides that repair membranes and counteract the action of perforin (PRF1) pores. Following cleavage by CASP1 in response to inflammasome activation, catalyzes processing and inactivation of PARP1, alleviating the transcription repressor activity of PARP1. Acts as an inhibitor of type I interferon production during virus-induced apoptosis by mediating cleavage of antiviral proteins CGAS, IRF3 and MAVS, thereby preventing cytokine overproduction. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Cleaves phospholipid scramblase proteins XKR4, XKR8 and XKR9. In case of infection, catalyzes cleavage of Kaposi sarcoma-associated herpesvirus protein ORF57, thereby preventing expression of viral lytic genes ; [Isoform Beta]: Lacks enzymatic activity.
• Tissue Specificity: Highly expressed in lung, skeletal muscle, liver, kidney, spleen and heart, and moderately in testis. No expression in the brain.
• KEGG Pathway:
  Efferocytosis (hsa04148)
  Apoptosis (hsa04210)
  Apoptosis - multiple species (hsa04215)
  Cytosolic D.-sensing pathway (hsa04623)
  TNF sig.ling pathway (hsa04668)
  Non-alcoholic fatty liver disease (hsa04932)
  Alzheimer disease (hsa05010)
  Pathways of neurodegeneration - multiple diseases (hsa05022)
  Pathogenic Escherichia coli infection (hsa05130)
  Salmonella infection (hsa05132)
  Pertussis (hsa05133)
  Legionellosis (hsa05134)
  Pathways in cancer (hsa05200)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  SMAC (DIABLO) binds to IAPs (R-HSA-111463)
  SMAC(DIABLO)-mediated dissociation of IAP (R-HSA-111464)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)
  SMAC, XIAP-regulated apoptotic response (R-HSA-111469)
  Caspase-mediated cleavage of cytoskeletal proteins (R-HSA-264870)
  Activation of caspases through apoptosome-mediated cleavage (R-HSA-111459)
• BioCyc Pathway: MetaCyc:HS09288-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Caspase-7 (CASP7).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Caspase-7 (CASP7).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Caspase-7 (CASP7).	[3]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the activity of Caspase-7 (CASP7).	[4]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Caspase-7 (CASP7).	[5]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the activity of Caspase-7 (CASP7).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Caspase-7 (CASP7).	[7]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Caspase-7 (CASP7).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Caspase-7 (CASP7).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the activity of Caspase-7 (CASP7).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Caspase-7 (CASP7).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the activity of Caspase-7 (CASP7).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the activity of Caspase-7 (CASP7).	[13]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Caspase-7 (CASP7).	[14]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Caspase-7 (CASP7).	[16]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the activity of Caspase-7 (CASP7).	[17]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Caspase-7 (CASP7).	[18]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Caspase-7 (CASP7).	[19]
Cannabidiol	DM0659E	Approved	Cannabidiol increases the expression of Caspase-7 (CASP7).	[20]
Bortezomib	DMNO38U	Approved	Bortezomib increases the activity of Caspase-7 (CASP7).	[21]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the activity of Caspase-7 (CASP7).	[22]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the activity of Caspase-7 (CASP7).	[23]
Etoposide	DMNH3PG	Approved	Etoposide increases the activity of Caspase-7 (CASP7).	[24]
Paclitaxel	DMLB81S	Approved	Paclitaxel increases the expression of Caspase-7 (CASP7).	[25]
Clozapine	DMFC71L	Approved	Clozapine increases the activity of Caspase-7 (CASP7).	[22]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Caspase-7 (CASP7).	[27]
Simvastatin	DM30SGU	Approved	Simvastatin increases the activity of Caspase-7 (CASP7).	[28]
Mitoxantrone	DMM39BF	Approved	Mitoxantrone increases the activity of Caspase-7 (CASP7).	[29]
Capsaicin	DMGMF6V	Approved	Capsaicin increases the activity of Caspase-7 (CASP7).	[30]
Sorafenib	DMS8IFC	Approved	Sorafenib increases the activity of Caspase-7 (CASP7).	[31]
Fluoxetine	DM3PD2C	Approved	Fluoxetine increases the activity of Caspase-7 (CASP7).	[22]
Sertraline	DM0FB1J	Approved	Sertraline increases the activity of Caspase-7 (CASP7).	[32]
Nefazodone	DM4ZS8M	Approved	Nefazodone increases the activity of Caspase-7 (CASP7).	[22]
Estrone	DM5T6US	Approved	Estrone increases the activity of Caspase-7 (CASP7).	[22]
Dactinomycin	DM2YGNW	Approved	Dactinomycin decreases the expression of Caspase-7 (CASP7).	[5]
Docetaxel	DMDI269	Approved	Docetaxel increases the activity of Caspase-7 (CASP7).	[33]
Dopamine	DMPGUCF	Approved	Dopamine increases the activity of Caspase-7 (CASP7).	[34]
Sevoflurane	DMC9O43	Approved	Sevoflurane increases the activity of Caspase-7 (CASP7).	[36]
Crizotinib	DM4F29C	Approved	Crizotinib increases the activity of Caspase-7 (CASP7).	[37]
Mebendazole	DMO14SG	Approved	Mebendazole increases the activity of Caspase-7 (CASP7).	[38]
Cimetidine	DMH61ZB	Approved	Cimetidine increases the activity of Caspase-7 (CASP7).	[39]
Mitotane	DMU1GX0	Approved	Mitotane increases the activity of Caspase-7 (CASP7).	[40]
Nilotinib	DM7HXWT	Approved	Nilotinib increases the activity of Caspase-7 (CASP7).	[37]
Lapatinib	DM3BH1Y	Approved	Lapatinib increases the activity of Caspase-7 (CASP7).	[41]
Propranolol	DM79NTF	Approved	Propranolol increases the activity of Caspase-7 (CASP7).	[22]
Imipramine	DM2NUH3	Approved	Imipramine increases the activity of Caspase-7 (CASP7).	[22]
Nelfinavir mesylate	DMFX6G8	Approved	Nelfinavir mesylate increases the activity of Caspase-7 (CASP7).	[42]
Clomipramine	DMINRKW	Approved	Clomipramine increases the activity of Caspase-7 (CASP7).	[22]
Etodolac	DM6WJO9	Approved	Etodolac increases the activity of Caspase-7 (CASP7).	[44]
Loratadine	DMF3AN7	Approved	Loratadine increases the activity of Caspase-7 (CASP7).	[22]
Flecainide	DMSQDLE	Approved	Flecainide increases the activity of Caspase-7 (CASP7).	[22]
Spironolactone	DM2AQ5N	Approved	Spironolactone increases the activity of Caspase-7 (CASP7).	[22]
Dronedarone	DMA8FS5	Approved	Dronedarone increases the activity of Caspase-7 (CASP7).	[45]
Cladribine	DM3JDRP	Approved	Cladribine increases the activity of Caspase-7 (CASP7).	[29]
Risperidone	DMN6DXL	Approved	Risperidone increases the activity of Caspase-7 (CASP7).	[22]
Dipyridamole	DMXY30O	Approved	Dipyridamole increases the activity of Caspase-7 (CASP7).	[22]
Nortriptyline	DM4KDYJ	Approved	Nortriptyline increases the activity of Caspase-7 (CASP7).	[22]
Pyrimethamine	DM5X7VY	Approved	Pyrimethamine increases the activity of Caspase-7 (CASP7).	[22]
Riluzole	DMECBWN	Approved	Riluzole increases the activity of Caspase-7 (CASP7).	[22]
Bendamustine hydrochloride	DMFH15Z	Approved	Bendamustine hydrochloride increases the activity of Caspase-7 (CASP7).	[29]
Phentolamine	DMXYJOB	Approved	Phentolamine increases the activity of Caspase-7 (CASP7).	[22]
Luvox	DMJKROX	Approved	Luvox increases the activity of Caspase-7 (CASP7).	[22]
Alpidem	DMN7Y9K	Approved	Alpidem increases the activity of Caspase-7 (CASP7).	[22]
Nimodipine	DMQ0RKZ	Approved	Nimodipine increases the activity of Caspase-7 (CASP7).	[22]
MCI-186	DM8ZHP1	Approved	MCI-186 increases the activity of Caspase-7 (CASP7).	[46]
Zileuton	DMVRIC2	Approved	Zileuton increases the activity of Caspase-7 (CASP7).	[22]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the activity of Caspase-7 (CASP7).	[47]
Curcumin	DMQPH29	Phase 3	Curcumin decreases the expression of Caspase-7 (CASP7).	[48]
Fenretinide	DMRD5SP	Phase 3	Fenretinide increases the activity of Caspase-7 (CASP7).	[49]
Camptothecin	DM6CHNJ	Phase 3	Camptothecin decreases the expression of Caspase-7 (CASP7).	[50]
Rigosertib	DMOSTXF	Phase 3	Rigosertib increases the activity of Caspase-7 (CASP7).	[51]
I3C	DMIGFOR	Phase 3	I3C decreases the expression of Caspase-7 (CASP7).	[52]
Triptolide	DMCMDVR	Phase 3	Triptolide increases the activity of Caspase-7 (CASP7).	[53]
Remdesivir	DMBFZ6L	Phase 3 Trial	Remdesivir decreases the expression of Caspase-7 (CASP7).	[54]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone increases the activity of Caspase-7 (CASP7).	[55]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the activity of Caspase-7 (CASP7).	[58]
Disulfiram	DMCL2OK	Phase 2 Trial	Disulfiram increases the activity of Caspase-7 (CASP7).	[59]
Gossypol	DMJWE3I	Phase 2	Gossypol increases the activity of Caspase-7 (CASP7).	[17]
STX-140	DMJK5CT	Phase 2	STX-140 increases the activity of Caspase-7 (CASP7).	[63]
G1	DMTV42K	Phase 1/2	G1 decreases the activity of Caspase-7 (CASP7).	[64]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Caspase-7 (CASP7).	[65]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the activity of Caspase-7 (CASP7).	[66]
AMEP	DMFELMQ	Phase 1	AMEP increases the expression of Caspase-7 (CASP7).	[69]
BETULINIC ACID	DMBUI2A	Phase 1	BETULINIC ACID increases the activity of Caspase-7 (CASP7).	[70]
IRX4204	DM9SCME	Phase 1	IRX4204 increases the activity of Caspase-7 (CASP7).	[71]
GSK525762	DMPAWBN	Phase 1	GSK525762 increases the activity of Caspase-7 (CASP7).	[72]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Caspase-7 (CASP7).	[73]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Caspase-7 (CASP7).	[74]
PMID26394986-Compound-22	DM43Z1G	Patented	PMID26394986-Compound-22 increases the activity of Caspase-7 (CASP7).	[75]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vorinostat	DMWMPD4	Approved	Vorinostat increases the cleavage of Caspase-7 (CASP7).	[15]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the cleavage of Caspase-7 (CASP7).	[26]
Nitric Oxide	DM1RBYG	Approved	Nitric Oxide decreases the cleavage of Caspase-7 (CASP7).	[35]
Omacetaxine mepesuccinate	DMPU2WX	Approved	Omacetaxine mepesuccinate increases the cleavage of Caspase-7 (CASP7).	[43]
Thymoquinone	DMVDTR2	Phase 2/3	Thymoquinone increases the cleavage of Caspase-7 (CASP7).	[56]
Belinostat	DM6OC53	Phase 2	Belinostat increases the cleavage of Caspase-7 (CASP7).	[57]
INK128	DMGO7QT	Phase 2	INK128 increases the cleavage of Caspase-7 (CASP7).	[60]
Fucoxanthin	DMPQFTA	Phase 2	Fucoxanthin increases the cleavage of Caspase-7 (CASP7).	[61]
PF-04991532	DM94NBE	Phase 2	PF-04991532 increases the cleavage of Caspase-7 (CASP7).	[62]
Mivebresib	DMCPF90	Phase 1	Mivebresib increases the cleavage of Caspase-7 (CASP7).	[67]
LY294002	DMY1AFS	Phase 1	LY294002 increases the cleavage of Caspase-7 (CASP7).	[68]

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