Target Information
Target General Information | Top | |||||
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Target ID |
T81892
(Former ID: TTDC00280)
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Target Name |
XIAP messenger RNA (XIAP mRNA)
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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)
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Gene Name |
XIAP
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Target Type |
Clinical trial target
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[1] | ||||
Disease | [+] 2 Target-related Diseases | + | ||||
1 | Lymphoma [ICD-11: 2A80-2A86] | |||||
2 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
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.
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BioChemical Class |
mRNA target
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UniProt ID | ||||||
EC Number |
EC 2.3.2.27
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Sequence |
MTFNSFEGSKTCVPADINKEEEFVEEFNRLKTFANFPSGSPVSASTLARAGFLYTGEGDT
VRCFSCHAAVDRWQYGDSAVGRHRKVSPNCRFINGFYLENSATQSTNSGIQNGQYKVENY LGSRDHFALDRPSETHADYLLRTGQVVDISDTIYPRNPAMYSEEARLKSFQNWPDYAHLT PRELASAGLYYTGIGDQVQCFCCGGKLKNWEPCDRAWSEHRRHFPNCFFVLGRNLNIRSE SDAVSSDRNFPNSTNLPRNPSMADYEARIFTFGTWIYSVNKEQLARAGFYALGEGDKVKC FHCGGGLTDWKPSEDPWEQHAKWYPGCKYLLEQKGQEYINNIHLTHSLEECLVRTTEKTP SLTRRIDDTIFQNPMVQEAIRMGFSFKDIKKIMEEKIQISGSNYKSLEVLVADLVNAQKD SMQDESSQTSLQKEISTEEQLRRLQEEKLCKICMDRNIAIVFVPCGHLVTCKQCAEAVDK CPMCYTVITFKQKIFMS Click to Show/Hide
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Drugs and Modes of Action | Top | |||||
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Clinical Trial Drug(s) | [+] 2 Clinical Trial Drugs | + | ||||
1 | ASTX660 | Drug Info | Phase 2 | Lymphoma | [1] | |
2 | AEG35156 | Drug Info | Phase 1/2 | Solid tumour/cancer | [2] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 8 Inhibitor drugs | + | ||||
1 | ASTX660 | Drug Info | [1] | |||
2 | EMBELIN | Drug Info | [4] | |||
3 | ARPFAQK-FAM | Drug Info | [4] | |||
4 | AVPIAQKSEK-FAM | Drug Info | [4] | |||
5 | BV-6 | Drug Info | [6] | |||
6 | SM-122 | Drug Info | [7] | |||
7 | SM-131 | Drug Info | [8] | |||
8 | SM-337 | Drug Info | [7] | |||
Antagonist | [+] 1 Antagonist drugs | + | ||||
1 | AZD5582 | Drug Info | [5] |
Cell-based Target Expression Variations | Top | |||||
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Cell-based Target Expression Variations |
Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
Co-Targets | Top | |||||
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Co-Targets |
Target Affiliated Biological Pathways | Top | |||||
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KEGG Pathway | [+] 8 KEGG Pathways | + | ||||
1 | NF-kappa B signaling pathway | |||||
2 | Ubiquitin mediated proteolysis | |||||
3 | Apoptosis | |||||
4 | Focal adhesion | |||||
5 | Toxoplasmosis | |||||
6 | HTLV-I infection | |||||
7 | Pathways in cancer | |||||
8 | Small cell lung cancer | |||||
Panther Pathway | [+] 1 Panther Pathways | + | ||||
1 | Apoptosis signaling pathway | |||||
PID Pathway | [+] 4 PID Pathways | + | ||||
1 | p75(NTR)-mediated signaling | |||||
2 | BMP receptor signaling | |||||
3 | Caspase Cascade in Apoptosis | |||||
4 | TGF-beta receptor signaling | |||||
Reactome | [+] 7 Reactome Pathways | + | ||||
1 | SMAC binds to IAPs | |||||
2 | SMAC-mediated dissociation of IAP:caspase complexes | |||||
3 | Deactivation of the beta-catenin transactivating complex | |||||
4 | RIPK1-mediated regulated necrosis | |||||
5 | Regulation of TNFR1 signaling | |||||
6 | TNFR1-induced NFkappaB signaling pathway | |||||
7 | Regulation of necroptotic cell death | |||||
WikiPathways | [+] 6 WikiPathways | + | ||||
1 | Copper homeostasis | |||||
2 | Focal Adhesion | |||||
3 | Apoptosis | |||||
4 | Intrinsic Pathway for Apoptosis | |||||
5 | Apoptosis Modulation and Signaling | |||||
6 | NOD pathway |
Target-Related Models and Studies | Top | |||||
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Target Validation |
References | Top | |||||
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REF 1 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
REF 2 | ClinicalTrials.gov (NCT00768339) A Phase 1-2, Multicenter, Open-Label Study of AEG35156 in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia and Indolent B-Cell Lymphomas. U.S. National Institutes of Health. | |||||
REF 3 | Teaming up to tackle RNAi delivery challenge. Nat Rev Drug Discov. 2009 Jul;8(7):525-6. | |||||
REF 4 | 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. | |||||
REF 5 | 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. | |||||
REF 6 | IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007 Nov 16;131(4):669-81. | |||||
REF 7 | Nonpeptidic and potent small-molecule inhibitors of cIAP-1/2 and XIAP proteins. J Med Chem. 2010 Sep 9;53(17):6361-7. | |||||
REF 8 | 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. |
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