Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTA8TVI8)

DOT Name Caspase-8 (CASP8)
Synonyms
CASP-8; EC 3.4.22.61; Apoptotic cysteine protease; Apoptotic protease Mch-5; CAP4; FADD-homologous ICE/ced-3-like protease; FADD-like ICE; FLICE; ICE-like apoptotic protease 5; MORT1-associated ced-3 homolog; MACH
Gene Name CASP8
Related Disease
Autoimmune lymphoproliferative syndrome type 2B ( )
UniProt ID
CASP8_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
1F9E; 1I4E; 1QDU; 1QTN; 2C2Z; 2FUN; 2K7Z; 2Y1L; 3H11; 3KJN; 3KJQ; 4JJ7; 4PRZ; 4PS1; 4ZBW; 5H31; 5H33; 5JQE; 5L08; 6AGW; 6PX9; 7DEE; 7LVJ; 7LVM
EC Number
3.4.22.61
Pfam ID
PF01335 ; PF00656
Sequence
MDFSRNLYDIGEQLDSEDLASLKFLSLDYIPQRKQEPIKDALMLFQRLQEKRMLEESNLS
FLKELLFRINRLDLLITYLNTRKEEMERELQTPGRAQISAYRVMLYQISEEVSRSELRSF
KFLLQEEISKCKLDDDMNLLDIFIEMEKRVILGEGKLDILKRVCAQINKSLLKIINDYEE
FSKERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGYCLIIN
NHNFAKAREKVPKLHSIRDRNGTHLDAGALTTTFEELHFEIKPHDDCTVEQIYEILKIYQ
LMDHSNMDCFICCILSHGDKGIIYGTDGQEAPIYELTSQFTGLKCPSLAGKPKVFFIQAC
QGDNYQKGIPVETDSEEQPYLEMDLSSPQTRYIPDEADFLLGMATVNNCVSYRNPAEGTW
YIQSLCQSLRERCPRGDDILTILTEVNYEVSNKDDKKNMGKQMPQPTFTLRKKLVFPSD
Function
Thiol protease that plays a key role in programmed cell death by acting as a molecular switch for apoptosis, necroptosis and pyroptosis, and is required to prevent tissue damage during embryonic development and adulthood. Initiator protease that induces extrinsic apoptosis by mediating cleavage and activation of effector caspases responsible for FAS/CD95-mediated and TNFRSF1A-induced cell death. Cleaves and activates effector caspases CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. Binding to the adapter molecule FADD recruits it to either receptor FAS/TNFRSF6 or TNFRSF1A. The resulting aggregate called the death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. In addition to extrinsic apoptosis, also acts as a negative regulator of necroptosis: acts by cleaving RIPK1 at 'Asp-324', which is crucial to inhibit RIPK1 kinase activity, limiting TNF-induced apoptosis, necroptosis and inflammatory response. Also able to initiate pyroptosis by mediating cleavage and activation of gasdermin-C and -D (GSDMC and GSDMD, respectively): gasdermin cleavage promotes release of the N-terminal moiety that binds to membranes and forms pores, triggering pyroptosis. Initiates pyroptosis following inactivation of MAP3K7/TAK1. Also acts as a regulator of innate immunity by mediating cleavage and inactivation of N4BP1 downstream of TLR3 or TLR4, thereby promoting cytokine production. May participate in the Granzyme B (GZMB) cell death pathways. Cleaves PARP1 and PARP2. Independent of its protease activity, promotes cell migration following phosphorylation at Tyr-380 ; [Isoform 5]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex; [Isoform 6]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex; [Isoform 7]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex (Probable). Acts as an inhibitor of the caspase cascade ; [Isoform 8]: Lacks the catalytic site and may interfere with the pro-apoptotic activity of the complex.
Tissue Specificity
Isoform 1, isoform 5 and isoform 7 are expressed in a wide variety of tissues. Highest expression in peripheral blood leukocytes, spleen, thymus and liver. Barely detectable in brain, testis and skeletal muscle.
KEGG Pathway
Platinum drug resistance (hsa01524 )
p53 sig.ling pathway (hsa04115 )
Apoptosis (hsa04210 )
Apoptosis - multiple species (hsa04215 )
Necroptosis (hsa04217 )
Toll-like receptor sig.ling pathway (hsa04620 )
NOD-like receptor sig.ling pathway (hsa04621 )
RIG-I-like receptor sig.ling pathway (hsa04622 )
Cytosolic D.-sensing pathway (hsa04623 )
C-type lectin receptor sig.ling pathway (hsa04625 )
IL-17 sig.ling pathway (hsa04657 )
TNF sig.ling pathway (hsa04668 )
Non-alcoholic fatty liver disease (hsa04932 )
Alcoholic liver disease (hsa04936 )
Alzheimer disease (hsa05010 )
Huntington disease (hsa05016 )
Pathways of neurodegeneration - multiple diseases (hsa05022 )
Pathogenic Escherichia coli infection (hsa05130 )
Salmonella infection (hsa05132 )
Legionellosis (hsa05134 )
Chagas disease (hsa05142 )
Toxoplasmosis (hsa05145 )
Tuberculosis (hsa05152 )
Hepatitis C (hsa05160 )
Hepatitis B (hsa05161 )
Measles (hsa05162 )
Human cytomegalovirus infection (hsa05163 )
Influenza A (hsa05164 )
Human papillomavirus infection (hsa05165 )
Kaposi sarcoma-associated herpesvirus infection (hsa05167 )
Herpes simplex virus 1 infection (hsa05168 )
Epstein-Barr virus infection (hsa05169 )
Human immunodeficiency virus 1 infection (hsa05170 )
Pathways in cancer (hsa05200 )
Viral carcinogenesis (hsa05203 )
Viral myocarditis (hsa05416 )
Lipid and atherosclerosis (hsa05417 )
Reactome Pathway
Caspase activation via Death Receptors in the presence of ligand (R-HSA-140534 )
NOD1/2 Signaling Pathway (R-HSA-168638 )
TRIF-mediated programmed cell death (R-HSA-2562578 )
Caspase-mediated cleavage of cytoskeletal proteins (R-HSA-264870 )
Regulation by c-FLIP (R-HSA-3371378 )
RIPK1-mediated regulated necrosis (R-HSA-5213460 )
CASP8 activity is inhibited (R-HSA-5218900 )
TNFR1-induced proapoptotic signaling (R-HSA-5357786 )
Regulation of TNFR1 signaling (R-HSA-5357905 )
CLEC7A/inflammasome pathway (R-HSA-5660668 )
Regulation of necroptotic cell death (R-HSA-5675482 )
Dimerization of procaspase-8 (R-HSA-69416 )
Activation, myristolyation of BID and translocation to mitochondria (R-HSA-75108 )
Apoptotic execution phase (R-HSA-75153 )
FasL/ CD95L signaling (R-HSA-75157 )
TRAIL signaling (R-HSA-75158 )
TLR3-mediated TICAM1-dependent programmed cell death (R-HSA-9013957 )
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 (R-HSA-933543 )
Microbial modulation of RIPK1-mediated regulated necrosis (R-HSA-9686347 )
Defective RIPK1-mediated regulated necrosis (R-HSA-9693928 )
Regulation of NF-kappa B signaling (R-HSA-9758274 )
Apoptotic cleavage of cellular proteins (R-HSA-111465 )
BioCyc Pathway
MetaCyc:HS00790-MONOMER

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Autoimmune lymphoproliferative syndrome type 2B DIS7EXGM Strong Autosomal recessive [1]
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Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
This DOT Affected the Drug Response of 4 Drug(s)
Drug Name Drug ID Highest Status Interaction REF
Dexamethasone DMMWZET Approved Caspase-8 (CASP8) increases the response to substance of Dexamethasone. [95]
Etoposide DMNH3PG Approved Caspase-8 (CASP8) decreases the response to substance of Etoposide. [96]
Cyclophosphamide DM4O2Z7 Approved Caspase-8 (CASP8) increases the response to substance of Cyclophosphamide. [95]
Thioguanine DM7NKEV Approved Caspase-8 (CASP8) increases the response to substance of Thioguanine. [95]
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85 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-8 (CASP8). [2]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Caspase-8 (CASP8). [3]
Acetaminophen DMUIE76 Approved Acetaminophen decreases the expression of Caspase-8 (CASP8). [4]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Caspase-8 (CASP8). [5]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate decreases the expression of Caspase-8 (CASP8). [6]
Cisplatin DMRHGI9 Approved Cisplatin increases the expression of Caspase-8 (CASP8). [7]
Estradiol DMUNTE3 Approved Estradiol increases the expression of Caspase-8 (CASP8). [8]
Ivermectin DMDBX5F Approved Ivermectin decreases the expression of Caspase-8 (CASP8). [9]
Arsenic DMTL2Y1 Approved Arsenic increases the expression of Caspase-8 (CASP8). [10]
Quercetin DM3NC4M Approved Quercetin decreases the expression of Caspase-8 (CASP8). [11]
Arsenic trioxide DM61TA4 Approved Arsenic trioxide increases the expression of Caspase-8 (CASP8). [13]
Hydrogen peroxide DM1NG5W Approved Hydrogen peroxide increases the activity of Caspase-8 (CASP8). [14]
Vorinostat DMWMPD4 Approved Vorinostat increases the expression of Caspase-8 (CASP8). [15]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Caspase-8 (CASP8). [16]
Methotrexate DM2TEOL Approved Methotrexate increases the expression of Caspase-8 (CASP8). [17]
Decitabine DMQL8XJ Approved Decitabine increases the expression of Caspase-8 (CASP8). [18]
Marinol DM70IK5 Approved Marinol decreases the expression of Caspase-8 (CASP8). [19]
Zoledronate DMIXC7G Approved Zoledronate increases the expression of Caspase-8 (CASP8). [20]
Selenium DM25CGV Approved Selenium decreases the expression of Caspase-8 (CASP8). [21]
Fluorouracil DMUM7HZ Approved Fluorouracil decreases the expression of Caspase-8 (CASP8). [22]
Panobinostat DM58WKG Approved Panobinostat increases the expression of Caspase-8 (CASP8). [15]
Folic acid DMEMBJC Approved Folic acid affects the expression of Caspase-8 (CASP8). [23]
Cannabidiol DM0659E Approved Cannabidiol decreases the expression of Caspase-8 (CASP8). [25]
Troglitazone DM3VFPD Approved Troglitazone decreases the expression of Caspase-8 (CASP8). [28]
Hydroquinone DM6AVR4 Approved Hydroquinone increases the activity of Caspase-8 (CASP8). [29]
Aspirin DM672AH Approved Aspirin increases the expression of Caspase-8 (CASP8). [30]
Irinotecan DMP6SC2 Approved Irinotecan increases the activity of Caspase-8 (CASP8). [31]
Paclitaxel DMLB81S Approved Paclitaxel increases the expression of Caspase-8 (CASP8). [32]
Diclofenac DMPIHLS Approved Diclofenac increases the activity of Caspase-8 (CASP8). [33]
Dasatinib DMJV2EK Approved Dasatinib increases the activity of Caspase-8 (CASP8). [34]
Menthol DMG2KW7 Approved Menthol decreases the expression of Caspase-8 (CASP8). [35]
Mitomycin DMH0ZJE Approved Mitomycin increases the activity of Caspase-8 (CASP8). [36]
Azacitidine DMTA5OE Approved Azacitidine increases the expression of Caspase-8 (CASP8). [37]
Simvastatin DM30SGU Approved Simvastatin increases the activity of Caspase-8 (CASP8). [38]
Topotecan DMP6G8T Approved Topotecan increases the activity of Caspase-8 (CASP8). [39]
Gemcitabine DMSE3I7 Approved Gemcitabine increases the activity of Caspase-8 (CASP8). [40]
Obeticholic acid DM3Q1SM Approved Obeticholic acid increases the expression of Caspase-8 (CASP8). [41]
Mitoxantrone DMM39BF Approved Mitoxantrone increases the activity of Caspase-8 (CASP8). [42]
Capsaicin DMGMF6V Approved Capsaicin increases the expression of Caspase-8 (CASP8). [44]
Alitretinoin DMME8LH Approved Alitretinoin increases the activity of Caspase-8 (CASP8). [45]
Vitamin C DMXJ7O8 Approved Vitamin C increases the expression of Caspase-8 (CASP8). [47]
Enzalutamide DMGL19D Approved Enzalutamide decreases the expression of Caspase-8 (CASP8). [48]
Ursodeoxycholic acid DMCUT21 Approved Ursodeoxycholic acid increases the activity of Caspase-8 (CASP8). [50]
Dactinomycin DM2YGNW Approved Dactinomycin decreases the expression of Caspase-8 (CASP8). [52]
Docetaxel DMDI269 Approved Docetaxel increases the activity of Caspase-8 (CASP8). [53]
Nitric Oxide DM1RBYG Approved Nitric Oxide increases the activity of Caspase-8 (CASP8). [54]
Lovastatin DM9OZWQ Approved Lovastatin increases the activity of Caspase-8 (CASP8). [38]
Melatonin DMKWFBT Approved Melatonin increases the activity of Caspase-8 (CASP8). [55]
Adenosine DMM2NSK Approved Adenosine increases the activity of Caspase-8 (CASP8). [56]
Gentamicin DMKINJO Approved Gentamicin increases the expression of Caspase-8 (CASP8). [57]
Morphine DMRMS0L Approved Morphine decreases the expression of Caspase-8 (CASP8). [58]
Ciprofloxacin XR DM2NLS9 Approved Ciprofloxacin XR increases the activity of Caspase-8 (CASP8). [60]
Cimetidine DMH61ZB Approved Cimetidine increases the activity of Caspase-8 (CASP8). [62]
Chlorambucil DMRKE63 Approved Chlorambucil increases the activity of Caspase-8 (CASP8). [63]
Sodium chloride DMM3950 Approved Sodium chloride increases the expression of Caspase-8 (CASP8). [64]
Busulfan DMXYJ9C Approved Busulfan increases the activity of Caspase-8 (CASP8). [65]
Nelfinavir mesylate DMFX6G8 Approved Nelfinavir mesylate increases the activity of Caspase-8 (CASP8). [66]
Masoprocol DMMVNZ0 Approved Masoprocol increases the expression of Caspase-8 (CASP8). [67]
Phenylephrine DMZHUO5 Approved Phenylephrine affects the activity of Caspase-8 (CASP8). [68]
Sanguinarine DMDINFS Approved Sanguinarine increases the activity of Caspase-8 (CASP8). [70]
Methoxsalen DME8FZ9 Approved Methoxsalen decreases the expression of Caspase-8 (CASP8). [71]
Fludarabine DMVRLT7 Approved Fludarabine increases the activity of Caspase-8 (CASP8). [63]
Clonidine DM6RZ9Q Approved Clonidine increases the activity of Caspase-8 (CASP8). [73]
Bupropion DM5PCS7 Approved Bupropion increases the activity of Caspase-8 (CASP8). [75]
Cladribine DM3JDRP Approved Cladribine increases the activity of Caspase-8 (CASP8). [76]
Pyrimethamine DM5X7VY Approved Pyrimethamine increases the activity of Caspase-8 (CASP8). [77]
Riluzole DMECBWN Approved Riluzole increases the activity of Caspase-8 (CASP8). [78]
Acitretin DM8BKU9 Approved Acitretin increases the activity of Caspase-8 (CASP8). [79]
Bendamustine hydrochloride DMFH15Z Approved Bendamustine hydrochloride increases the activity of Caspase-8 (CASP8). [42]
Regorafenib DMHSY1I Approved Regorafenib increases the activity of Caspase-8 (CASP8). [80]
Niflumic acid DMJ3I1Q Approved Niflumic acid increases the activity of Caspase-8 (CASP8). [81]
Aminolevulinic acid hci DMS4BLQ Approved Aminolevulinic acid hci increases the activity of Caspase-8 (CASP8). [82]
Aclarubicin DMLFZHD Approved Aclarubicin increases the activity of Caspase-8 (CASP8). [83]
Norfloxacin DMIZ6W2 Approved Norfloxacin affects the activity of Caspase-8 (CASP8). [84]
Vitamin B6 DMDBZMV Approved Vitamin B6 increases the expression of Caspase-8 (CASP8). [86]
Berberine DMC5Q8X Phase 4 Berberine increases the activity of Caspase-8 (CASP8). [87]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Caspase-8 (CASP8). [15]
Resveratrol DM3RWXL Phase 3 Resveratrol increases the expression of Caspase-8 (CASP8). [88]
Curcumin DMQPH29 Phase 3 Curcumin decreases the expression of Caspase-8 (CASP8). [89]
Camptothecin DM6CHNJ Phase 3 Camptothecin decreases the expression of Caspase-8 (CASP8). [5]
Atorvastatin DMF28YC Phase 3 Trial Atorvastatin increases the activity of Caspase-8 (CASP8). [38]
HMPL-004 DM29XGY Phase 3 HMPL-004 increases the expression of Caspase-8 (CASP8). [90]
Bardoxolone methyl DMODA2X Phase 3 Bardoxolone methyl decreases the expression of Caspase-8 (CASP8). [91]
EXISULIND DMBY56U Phase 3 EXISULIND increases the activity of Caspase-8 (CASP8). [93]
Glycyrrhizin DM8M2N3 Phase 3 Glycyrrhizin increases the activity of Caspase-8 (CASP8). [94]
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⏷ Show the Full List of 85 Drug(s)
15 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT
Drug Name Drug ID Highest Status Interaction REF
Temozolomide DMKECZD Approved Temozolomide increases the cleavage of Caspase-8 (CASP8). [12]
Niclosamide DMJAGXQ Approved Niclosamide increases the cleavage of Caspase-8 (CASP8). [24]
Isotretinoin DM4QTBN Approved Isotretinoin increases the cleavage of Caspase-8 (CASP8). [26]
Bortezomib DMNO38U Approved Bortezomib increases the cleavage of Caspase-8 (CASP8). [27]
Zidovudine DM4KI7O Approved Zidovudine increases the cleavage of Caspase-8 (CASP8). [43]
Thalidomide DM70BU5 Approved Thalidomide increases the cleavage of Caspase-8 (CASP8). [46]
Sorafenib DMS8IFC Approved Sorafenib increases the cleavage of Caspase-8 (CASP8). [49]
Gefitinib DM15F0X Approved Gefitinib increases the cleavage of Caspase-8 (CASP8). [51]
Crizotinib DM4F29C Approved Crizotinib increases the cleavage of Caspase-8 (CASP8). [59]
Omeprazole DM471KJ Approved Omeprazole increases the cleavage of Caspase-8 (CASP8). [61]
Ethacrynic acid DM60QMR Approved Ethacrynic acid increases the cleavage of Caspase-8 (CASP8). [69]
Loratadine DMF3AN7 Approved Loratadine increases the cleavage of Caspase-8 (CASP8). [72]
Digitoxin DMWVIGP Approved Digitoxin increases the cleavage of Caspase-8 (CASP8). [74]
Trifluridine DMG2YBD Approved Trifluridine increases the cleavage of Caspase-8 (CASP8). [85]
Chloroquine DMSI5CB Phase 3 Trial Chloroquine increases the cleavage of Caspase-8 (CASP8). [92]
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⏷ Show the Full List of 15 Drug(s)

References

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36 Mitomycin C induces apoptosis in a caspases-dependent and Fas/CD95-independent manner in human gastric adenocarcinoma cells. Cancer Lett. 2000 Oct 1;158(2):125-32. doi: 10.1016/s0304-3835(00)00489-4.
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38 Statins activate the mitochondrial pathway of apoptosis in human lymphoblasts and myeloma cells. Carcinogenesis. 2005 May;26(5):883-91. doi: 10.1093/carcin/bgi036. Epub 2005 Feb 10.
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