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

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.

• Authors: Wei-Sheng Huang, 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 15 Pg. 4743-56 (Aug 13 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19572547 (Publication Type: Journal Article)

Chemical References

• Protein Kinase Inhibitors
• Purines
• Proto-Oncogene Proteins c-abl
• src-Family Kinases

Topics

• Animals
• Drug Design
• Female
• Humans
• K562 Cells
• Mice
• NIH 3T3 Cells
• Protein Conformation
• Protein Kinase Inhibitors (chemical synthesis, pharmacokinetics, pharmacology)
• Proto-Oncogene Proteins c-abl (antagonists & inhibitors, chemistry)
• Purines (chemical synthesis, pharmacology)
• Rats
• Structure-Activity Relationship
• src-Family Kinases (antagonists & inhibitors, chemistry)