3uw5
From Proteopedia
Crystal structure of the BIR domain of MLIAP bound to GDC0152
Structural highlights
Function[BIRC7_HUMAN] Apoptotic regulator capable of exerting proapoptotic and anti-apoptotic activities and plays crucial roles in apoptosis, cell proliferation, and cell cycle control. Its anti-apoptotic activity is mediated through the inhibition of CASP3, CASP7 and CASP9, as well as by its E3 ubiquitin-protein ligase activity. As it is a weak caspase inhibitor, its anti-apoptotic activity is thought to be due to its ability to ubiquitinate DIABLO/SMAC targeting it for degradation thereby promoting cell survival. May contribute to caspase inhibition, by blocking the ability of DIABLO/SMAC to disrupt XIAP/BIRC4-caspase interactions. Protects against apoptosis induced by TNF or by chemical agents such as adriamycin, etoposide or staurosporine. Suppression of apoptosis is mediated by activation of MAPK8/JNK1, and possibly also of MAPK9/JNK2. This activation depends on TAB1 and NR2C2/TAK1. In vitro, inhibits CASP3 and proteolytic activation of pro-CASP9. Isoform 1 blocks staurosporine-induced apoptosis. Isoform 2 blocks etoposide-induced apoptosis. Isoform 2 protects against natural killer (NK) cell killing whereas isoform 1 augments killing.[1] [2] [3] [4] 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[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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