Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTEVCT0)

• DTT Name: Caspase-8 (CASP8)
• Synonyms: MORT1-associated CED-3 homolog; MCH5; MACH; ICE-like apoptotic protease 5; FLICE; FADD-like ICE; FADD-homologous ICE/CED-3-like protease; CASP-8; CAP4; Apoptotic protease Mch-5; Apoptotic cysteine protease
• Gene Name: CASP8
• DTT Type: Patented-recorded target; [1]
• BioChemical Class: Peptidase
• UniProt ID: CASP8_HUMAN
• TTD ID: T15700
• EC Number: EC 3.4.22.61
• Sequence:
  MDFSRNLYDIGEQLDSEDLASLKFLSLDYIPQRKQEPIKDALMLFQRLQEKRMLEESNLS
  FLKELLFRINRLDLLITYLNTRKEEMERELQTPGRAQISAYRVMLYQISEEVSRSELRSF
  KFLLQEEISKCKLDDDMNLLDIFIEMEKRVILGEGKLDILKRVCAQINKSLLKIINDYEE
  FSKERSSSLEGSPDEFSNGEELCGVMTISDSPREQDSESQTLDKVYQMKSKPRGYCLIIN
  NHNFAKAREKVPKLHSIRDRNGTHLDAGALTTTFEELHFEIKPHDDCTVEQIYEILKIYQ
  LMDHSNMDCFICCILSHGDKGIIYGTDGQEAPIYELTSQFTGLKCPSLAGKPKVFFIQAC
  QGDNYQKGIPVETDSEEQPYLEMDLSSPQTRYIPDEADFLLGMATVNNCVSYRNPAEGTW
  YIQSLCQSLRERCPRGDDILTILTEVNYEVSNKDDKKNMGKQMPQPTFTLRKKLVFPSD
• Function: Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called 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. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex. Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death.
• KEGG Pathway:
  p53 signaling pathway (hsa04115)
  Apoptosis (hsa04210)
  Toll-like receptor signaling pathway (hsa04620)
  NOD-like receptor signaling pathway (hsa04621)
  RIG-I-like receptor signaling pathway (hsa04622)
  TNF signaling pathway (hsa04668)
  Non-alcoholic fatty liver disease (NAFLD) (hsa04932)
  Alzheimer's disease (hsa05010)
  Huntington's disease (hsa05016)
  Legionellosis (hsa05134)
  Chagas disease (American trypanosomiasis) (hsa05142)
  Toxoplasmosis (hsa05145)
  Tuberculosis (hsa05152)
  Hepatitis B (hsa05161)
  Herpes simplex infection (hsa05168)
  Pathways in cancer (hsa05200)
  Viral carcinogenesis (hsa05203)
  Viral myocarditis (hsa05416)
• Reactome Pathway:
  Ligand-dependent caspase activation (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)
  FasL/ CD95L signaling (R-HSA-75157)
  TRAIL signaling (R-HSA-75158)
  NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 (R-HSA-933543)
  Apoptotic cleavage of cellular proteins (R-HSA-111465)

Molecular Interaction Atlas (MIA) of This DTT

3 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acetyl-Ile-Glu-Thr-Asp-aldehyde	DM1VE6S	Discovery agent	N.A.	Investigative	[2]
Amooranin	DMC15DM	Autoimmune diabetes	5A10	Investigative	[3]
Glionitrin A	DM98CSW	Solid tumour/cancer	2A00-2F9Z	Investigative	[3]

References

• [1] Caspase inhibitors: a review of recently patented compounds (2013-2015).Expert Opin Ther Pat. 2018 Jan;28(1):47-59.
• [2] The atomic-resolution structure of human caspase-8, a key activator of apoptosis. Structure. 1999 Sep 15;7(9):1135-43.
• [3] Glionitrin A, a new diketopiperazine disulfide, activates ATM-ATR-Chk1/2 via 53BP1 phosphorylation in DU145 cells and shows antitumor effect in xenograft model. Biol Pharm Bull. 2014;37(3):378-86.