9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation

  • J Med Chem. 2009 Aug 13;52(15):4743-56. doi: 10.1021/jm900166t.
Wei-Sheng Huang  1 ,  Xiaotian Zhu ,  Yihan Wang ,  Mohammad Azam ,  David Wen ,  Raji Sundaramoorthi ,  R Mathew Thomas ,  Shuangying Liu ,  Geetha Banda ,  Scott P Lentini ,  Sasmita Das ,  Qihong Xu ,  Jeff Keats ,  Frank Wang ,  Scott Wardwell ,  Yaoyu Ning ,  Joseph T Snodgrass ,  Marc I Broudy ,  Karin Russian ,  George Q Daley ,  John Iuliucci ,  David C Dalgarno ,  Tim Clackson ,  Tomi K Sawyer ,  William C Shakespeare
Affiliations
  • 1. ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139, USA. [email protected]
PMID: 19572547 DOI: 10.1021/jm900166t
Abstract

A novel series of potent dual Src/Abl kinase inhibitors based on a 9-(arenethenyl)purine core has been identified. Unlike traditional dual Src/Abl inhibitors targeting the active enzyme conformation, these inhibitors bind to the inactive, DFG-out conformation of both Kinases. Extensive SAR studies led to the discovery of potent and orally bioavailable inhibitors, some of which demonstrated in vivo efficacy. Once-daily oral administration of inhibitor 9i (AP24226) significantly prolonged the survival of mice injected intravenously with wild type Bcr-Abl expressing Ba/F3 cells at a dose of 10 mg/kg. In a separate model, oral administration of 9i to mice bearing subcutaneous xenografts of Src Y527F expressing NIH 3T3 cells elicited dose-dependent tumor shrinkage with complete tumor regression observed at the highest dose. Notably, several inhibitors (e.g., 14a, AP24163) exhibited modest cellular potency (IC50 = 300-400 nM) against the Bcr-Abl mutant T315I, a variant resistant to all currently marketed therapies for chronic myeloid leukemia.

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