3uw4 | pdb_00003uw4
Crystal structure of cIAP1 BIR3 bound to GDC0152
Structural highlights
Function[BIRC2_HUMAN] 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 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.[1] [2] [3] [4] [5] Publication Abstract from PubMedA series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with Ki values of 28, 14, 17 and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 +/- 3 mL/min/kg and volume of distribution was 0.6 +/- 0.2 L/kg. The Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152).,Flygare J, Beresini M, Budha N, Chan H, Chan I, Cheeti S, Cohen F, Deshayes K, Doerner K, Eckhardt G, Elliott LO, Feng B, Franklin M, Reisner S, Gazzard L, Halladay J, Hymowitz SG, La H, Lorusso P, Maurer B, Murray L, Plise E, Quan C, Stephan JP, Young S, Tom J, Tsui V, Um J, Varfolomeev E, Vucic D, Wagner A, Wallweber H, Wang L, Ware J, Wen Z, Wong H, Wong J, Wong M, Wong S, Yu R, Zobel K, Fairbrother WJ J Med Chem. 2012 Mar 13. PMID:22413863[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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