3UW5

Crystal structure of the BIR domain of MLIAP bound to GDC0152

Summary for 3UW5

• Entry DOI: 10.2210/pdb3uw5/pdb
• Related PRD ID: PRD_001020
• Descriptor: Baculoviral IAP repeat-containing protein 7, Baculoviral IAP repeat-containing protein 4, GDC-0152, ZINC ION, ... (5 entities in total)
• Functional Keywords: apoptosis inhibitor, bir domain
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P98170
• Total number of polymer chains: 4
• Total formula weight: 27465.27

Authors

Maurer, B.,Hymowitz, S.G. (deposition date: 2011-11-30, release date: 2012-02-22, Last modification date: 2017-08-02)

Primary citation

Flygare, J.A.,Beresini, M.,Budha, N.,Chan, H.,Chan, I.T.,Cheeti, S.,Cohen, F.,Deshayes, K.,Doerner, K.,Eckhardt, S.G.,Elliott, L.O.,Feng, B.,Franklin, M.C.,Reisner, S.F.,Gazzard, L.,Halladay, J.,Hymowitz, S.G.,La, H.,Lorusso, P.,Maurer, B.,Murray, L.,Plise, E.,Quan, C.,Stephan, J.P.,Young, S.G.,Tom, J.,Tsui, V.,Um, J.,Varfolomeev, E.,Vucic, D.,Wagner, A.J.,Wallweber, H.J.,Wang, L.,Ware, J.,Wen, Z.,Wong, H.,Wong, J.M.,Wong, M.,Wong, S.,Yu, R.,Zobel, K.,Fairbrother, W.J.
Discovery of a Potent Small-Molecule Antagonist of Inhibitor of Apoptosis (IAP) Proteins and Clinical Candidate for the Treatment of Cancer (GDC-0152).
J.Med.Chem., 55:4101-4113, 2012

PubMed Abstract: A 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 K(i) 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 the volume of distribution was 0.6 ± 0.2 L/kg.

PubMed: 22413863
DOI: 10.1021/jm300060k

Experimental method

X-RAY DIFFRACTION (1.71 Å)