Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTK3WBU)

• DTT Name: XIAP messenger RNA (XIAP mRNA)
• Synonyms: hILP (mRNA); hIAP3 (mRNA); hIAP-3 (mRNA); Xlinked IAP (mRNA); X-linked IAP (mRNA); RING-type E3 ubiquitin transferase XIAP (mRNA); Inhibitor of apoptosis protein 3 (mRNA); ILP (mRNA); IAPlike protein (mRNA); IAP3 (mRNA); IAP-like protein (mRNA); IAP-3 (mRNA); E3 ubiquitinprotein ligase XIAP (mRNA); E3 ubiquitin-protein ligase XIAP (mRNA); Baculoviral IAP repeatcontaining protein 4 (mRNA); Baculoviral IAP repeat-containing protein 4 (mRNA); BIRC4 (mRNA); API3 (mRNA)
• Gene Name: XIAP
• DTT Type: Clinical trial target; [1]
• BioChemical Class: mRNA target
• UniProt ID: XIAP_HUMAN
• TTD ID: T81892
• EC Number: EC 2.3.2.27
• Sequence:
  MTFNSFEGSKTCVPADINKEEEFVEEFNRLKTFANFPSGSPVSASTLARAGFLYTGEGDT
  VRCFSCHAAVDRWQYGDSAVGRHRKVSPNCRFINGFYLENSATQSTNSGIQNGQYKVENY
  LGSRDHFALDRPSETHADYLLRTGQVVDISDTIYPRNPAMYSEEARLKSFQNWPDYAHLT
  PRELASAGLYYTGIGDQVQCFCCGGKLKNWEPCDRAWSEHRRHFPNCFFVLGRNLNIRSE
  SDAVSSDRNFPNSTNLPRNPSMADYEARIFTFGTWIYSVNKEQLARAGFYALGEGDKVKC
  FHCGGGLTDWKPSEDPWEQHAKWYPGCKYLLEQKGQEYINNIHLTHSLEECLVRTTEKTP
  SLTRRIDDTIFQNPMVQEAIRMGFSFKDIKKIMEEKIQISGSNYKSLEVLVADLVNAQKD
  SMQDESSQTSLQKEISTEEQLRRLQEEKLCKICMDRNIAIVFVPCGHLVTCKQCAEAVDK
  CPMCYTVITFKQKIFMS
• Function: Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program. Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis.
• KEGG Pathway:
  NF-kappa B signaling pathway (hsa04064)
  Ubiquitin mediated proteolysis (hsa04120)
  Apoptosis (hsa04210)
  Focal adhesion (hsa04510)
  Toxoplasmosis (hsa05145)
  HTLV-I infection (hsa05166)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
• Reactome Pathway:
  SMAC-mediated dissociation of IAP (R-HSA-111464)
  Deactivation of the beta-catenin transactivating complex (R-HSA-3769402)
  RIPK1-mediated regulated necrosis (R-HSA-5213460)
  Regulation of TNFR1 signaling (R-HSA-5357905)
  TNFR1-induced NFkappaB signaling pathway (R-HSA-5357956)
  Regulation of necroptotic cell death (R-HSA-5675482)
  SMAC binds to IAPs (R-HSA-111463)

Molecular Interaction Atlas (MIA) of This DTT

2 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ASTX660	DMMKW8L	Lymphoma	2A80-2A86	Phase 2	[1]
AEG35156	DM2HRYD	Solid tumour/cancer	2A00-2F9Z	Phase 1/2	[2]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
EMBELIN	DMFZO4Y	N. A.	N. A.	Terminated	[3]

7 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ARPFAQK-FAM	DMU70YP	Discovery agent	N.A.	Investigative	[3]
AVPIAQKSEK-FAM	DMNQ9R4	Discovery agent	N.A.	Investigative	[3]
AZD5582	DMPIHN6	Discovery agent	N.A.	Investigative	[4]
BV-6	DMDTV7A	Discovery agent	N.A.	Investigative	[5]
SM-122	DMC7YQE	Discovery agent	N.A.	Investigative	[6]
SM-131	DMP8VO6	Discovery agent	N.A.	Investigative	[7]
SM-337	DMOSTP9	Discovery agent	N.A.	Investigative	[6]

References

• [1] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [2] Teaming up to tackle RNAi delivery challenge. Nat Rev Drug Discov. 2009 Jul;8(7):525-6.
• [3] Discovery of embelin as a cell-permeable, small-molecular weight inhibitor of XIAP through structure-based computational screening of a traditional... J Med Chem. 2004 May 6;47(10):2430-40.
• [4] Discovery of a novel class of dimeric Smac mimetics as potent IAP antagonists resulting in a clinical candidate for the treatment of cancer (AZD5582). J Med Chem. 2013 Dec 27;56(24):9897-919.
• [5] IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007 Nov 16;131(4):669-81.
• [6] Nonpeptidic and potent small-molecule inhibitors of cIAP-1/2 and XIAP proteins. J Med Chem. 2010 Sep 9;53(17):6361-7.
• [7] Design, synthesis, and evaluation of tricyclic, conformationally constrained small-molecule mimetics of second mitochondria-derived activator of ca... J Med Chem. 2008 Dec 11;51(23):7352-5.