- 9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: Design, synthesis, and biological evaluation
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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. 2009 American Chemical Society.
- Huang, Wei-Sheng,Zhu, Xiaotian,Wang, Yihan,Azam, Mohammad,Wen, David,Sundaramoorthi, Raji,Thomas, R. Mathew,Liu, Shuangying,Banda, Geetha,Lentini, Scott P.,Das, Sasmita,Xu, Qihong,Keats, Jeff,Wang, Frank,Wardwell, Scott,Ning, Yaoyu,Snodgrass, Joseph T.,Broudy, Marc I.,Russian, Karin,Daley, George Q.,Iuliucci, John,Dalgarno, David C.,Clackson, Tim,Sawyer, Tomi K.,Shakespeare, William C.
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experimental part
p. 4743 - 4756
(2010/03/03)
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- Novel N9-arenethenyl purines as potent dual Src/Abl tyrosine kinase inhibitors
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Novel N9-arenethenyl purines, optimized potent dual Src/Abl tyrosine kinase inhibitors, are described. The key structural feature is a trans vinyl linkage at N9 on the purine core which projects hydrophobic substituents into the sele
- Wang, Yihan,Shakespeare, William C.,Huang, Wei-Sheng,Sundaramoorthi, Raji,Lentini, Scott,Das, Sasmita,Liu, Shuangying,Banda, Geeta,Wen, David,Zhu, Xiaotian,Xu, Qihong,Keats, Jeffrey,Wang, Frank,Wardwell, Scott,Ning, Yaoyu,Snodgrass, Joseph T.,Broudy, Mark I.,Russian, Karin,Dalgarno, David,Clackson, Tim,Sawyer, Tomi K.
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scheme or table
p. 4907 - 4912
(2009/05/30)
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