Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT6SZNG)

• DTT Name: Caspase 8 messenger RNA (CASP8 mRNA)
• Synonyms: MORT1-associated CED-3 homolog (mRNA); MCH5 (mRNA); MACH (mRNA); ICE-like apoptotic protease 5 (mRNA); FLICE (mRNA); FADD-like ICE (mRNA); FADD-homologous ICE/CED-3-like protease (mRNA); CASP-8 (mRNA); CAP4 (mRNA); Apoptotic protease Mch-5 (mRNA); Apoptotic cysteine protease (mRNA)
• Gene Name: CASP8
• DTT Type: Literature-reported target; [1]
• BioChemical Class: mRNA target
• UniProt ID: CASP8_HUMAN
• TTD ID: T28705
• 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

7 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]
ISIS 107612	DMBWCZR	Discovery agent	N.A.	Investigative	[1]
ISIS 107642	DMPR7OD	Discovery agent	N.A.	Investigative	[1]
ISIS 107652	DMOX8JF	Discovery agent	N.A.	Investigative	[1]
ISIS 107676	DMUE64H	Discovery agent	N.A.	Investigative	[1]
ISIS 107681	DMB9VFS	Discovery agent	N.A.	Investigative	[1]
Isoquinoline-1,3,4(2H)-trione	DMT4RI2	Discovery agent	N.A.	Investigative	[3]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Rheumatoid arthritis	FA20	Synovial tissue	8.78E-06	1.43	4.51

References

• [1] US patent application no. 6,258,600, Antisense modulation of caspase 8 expression.
• [2] Synthesis and in vitro evaluation of sulfonamide isatin Michael acceptors as small molecule inhibitors of caspase-6. J Med Chem. 2009 Apr 23;52(8):2188-91.
• [3] Design, synthesis, and biological evaluation of isoquinoline-1,3,4-trione derivatives as potent caspase-3 inhibitors. J Med Chem. 2006 Mar 9;49(5):1613-23.