2. Academic Validation
  3. 9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation

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

Affiliation

  • 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-14142
    Scr/ABL Inhibitor