Target General Infomation
Target ID
T84780
Former ID
TTDI02025
Target Name
Inhibitor of apoptosis protein 2
Gene Name
BIRC2
Synonyms
Baculoviral IAP repeatcontaining protein 2; CIAP1; IAP homolog B; IAP2; RING finger protein 48; TNFR2TRAFsignaling complex protein 2; hIAP2; BIRC2
Target Type
Clinical Trial
Disease Lymphoma [ICD9: 202.8, 208.9; ICD10: C81-C86]
Function
Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, mitogenic kinase signaling, and cell proliferation, as well as cell invasion and metastasis. Acts as an E3 ubiquitin- protein ligase regulating NF-kappa-B signaling and regulates both canonical and non-canonical NF-kappa-B signaling by acting in opposite directions: acts as a positive regulator of the canonical pathway and suppresses constitutive activation of non-canonical NF-kappa-B signaling. The target proteins for its E3 ubiquitin- protein ligase activity include: RIPK1, RIPK2, RIPK3, RIPK4, CASP3, CASP7, CASP8, TRAF2, DIABLO/SMAC, MAP3K14/NIK, MAP3K5/ASK1, IKBKG/NEMO, IKBKE and MXD1/MAD1. Can also function as an E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Acts as an important regulator of innate immune signaling via regulation of Toll-like receptors (TLRs), Nodlike receptors (NLRs) and RIG-I like receptors (RLRs),collectively referred to as pattern recognition receptors (PRRs). 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. Can stimulate the transcriptional activity of E2F1. Plays a role in the modulation of the cell cycle.
BioChemical Class
Carbon-nitrogen ligase
UniProt ID
EC Number
EC 6.3.2.-
Sequence
MHKTASQRLFPGPSYQNIKSIMEDSTILSDWTNSNKQKMKYDFSCELYRMSTYSTFPAGV
PVSERSLARAGFYYTGVNDKVKCFCCGLMLDNWKLGDSPIQKHKQLYPSCSFIQNLVSAS
LGSTSKNTSPMRNSFAHSLSPTLEHSSLFSGSYSSLSPNPLNSRAVEDISSSRTNPYSYA
MSTEEARFLTYHMWPLTFLSPSELARAGFYYIGPGDRVACFACGGKLSNWEPKDDAMSEH
RRHFPNCPFLENSLETLRFSISNLSMQTHAARMRTFMYWPSSVPVQPEQLASAGFYYVGR
NDDVKCFCCDGGLRCWESGDDPWVEHAKWFPRCEFLIRMKGQEFVDEIQGRYPHLLEQLL
STSDTTGEENADPPIIHFGPGESSSEDAVMMNTPVVKSALEMGFNRDLVKQTVQSKILTT
GENYKTVNDIVSALLNAEDEKREEEKEKQAEEMASDDLSLIRKNRMALFQQLTCVLPILD
NLLKANVINKQEHDIIKQKTQIPLQARELIDTILVKGNAAANIFKNCLKEIDSTLYKNLF
VDKNMKYIPTEDVSGLSLEEQLRRLQEERTCKVCMDKEVSVVFIPCGHLVVCQECAPSLR
KCPICRGIIKGTVRTFLS
Drugs and Mode of Action
Drug(s) Birinapant Drug Info Phase 2 Lymphoma [524774], [542455]
Debio 1143 Drug Info Phase 1/2 Lymphoma [524580]
Antagonist AZD5582 Drug Info [532581]
Modulator Birinapant Drug Info [532662], [532682]
Inhibitor BV-6 Drug Info [529155]
Debio 1143 Drug Info [533079], [544451]
Pathways
KEGG Pathway NF-kappa B signaling pathway
Ubiquitin mediated proteolysis
Apoptosis
Hippo signaling pathway
Focal adhesion
NOD-like receptor signaling pathway
TNF signaling pathway
Toxoplasmosis
Pathways in cancer
Small cell lung cancer
NetPath Pathway TCR Signaling Pathway
PANTHER Pathway Apoptosis signaling pathway
CCKR signaling map ST
Pathway Interaction Database Canonical NF-kappaB pathway
CD40/CD40L signaling
FAS (CD95) signaling pathway
TNF receptor signaling pathway
p75(NTR)-mediated signaling
Reactome Apoptotic cleavage of cellular proteins
NOD1/2 Signaling Pathway
RIPK1-mediated regulated necrosis
Regulation of TNFR1 signaling
TNFR1-induced NFkappaB signaling pathway
TNFR2 non-canonical NF-kB pathway
Regulation of necroptotic cell death
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway
IKK complex recruitment mediated by RIP1
WikiPathways Focal Adhesion
Apoptosis
TNF alpha Signaling Pathway
TWEAK Signaling Pathway
Apoptotic execution phase
Apoptosis Modulation and Signaling
References
Ref 524580ClinicalTrials.gov (NCT02022098) Debio 1143-201 Dose-finding and Efficacy Phase I/II Trial. U.S. National Institutes of Health.
Ref 524774ClinicalTrials.gov (NCT02147873) Study of Azacitidine With or Without Birinapant in Subjects With MDS or CMMoL. U.S. National Institutes of Health.
Ref 542455(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7432).
Ref 529155IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell. 2007 Nov 16;131(4):669-81.
Ref 532581Discovery 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 532662cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner. Blood. 2014 Apr 17;123(16):2562-72.
Ref 532682Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-?B activation, and is active in patient-derived xenograft models. Mol Cancer Ther. 2014 Apr;13(4):867-79.
Ref 533079Debio 1143, an antagonist of multiple inhibitor-of-apoptosis proteins, activates apoptosis and enhances radiosensitization of non-small cell lung cancer cells in vitro. Am J Cancer Res. 2014 Nov 19;4(6):943-51. eCollection 2014.
Ref 544451Debio 1143, an antagonist of multiple inhibitor-of-apoptosis proteins, activates apoptosis and enhances radiosensitization of non-small cell lung cancer cells in vitro. Am J Cancer Res. 2014; 4(6): 943-951.

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