2. Academic Validation
  3. Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152)

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. 2012 May 10;55(9):4101-13. doi: 10.1021/jm300060k.
John A Flygare 1,  Maureen Beresini,  Nageshwar Budha,  Helen Chan,  Iris T Chan,  Sravanthi Cheeti,  Frederick Cohen,  Kurt Deshayes,  Karl Doerner,  S Gail Eckhardt,  Linda O Elliott,  Bainian Feng,  Matthew C Franklin,  Stacy Frankovitz Reisner,  Lewis Gazzard,  Jason Halladay,  Sarah G Hymowitz,  Hank La,  Patricia LoRusso,  Brigitte Maurer,  Lesley Murray,  Emile Plise,  Clifford Quan,  Jean-Philippe Stephan,  Shin G Young,  Jeffrey Tom,  Vickie Tsui,  Joanne Um,  Eugene Varfolomeev,  Domagoj Vucic,  Andrew J Wagner,  Heidi J A Wallweber,  Lan Wang,  Joseph Ware,  Zhaoyang Wen,  Harvey Wong,  Jonathan M Wong,  Melisa Wong,  Susan Wong,  Ron Yu,  Kerry Zobel,  Wayne J Fairbrother
Affiliations

Affiliation

  • 1 Department of Discovery Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. jflygare@gene.com
PMID: 22413863 DOI: 10.1021/jm300060k
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13638
    99.67%, IAP抑制剂
    IAP
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