9-(Arenethenyl)purines as dual Src/Abl kinase inhibitors targeting the inactive conformation: design, synthesis, and biological evaluation.
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.
Huang
Wei-Sheng
WS
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139, USA. wei-sheng.huang@ariad.com
Zhu
Xiaotian
X
Wang
Yihan
Y
Azam
Mohammad
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Wen
David
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Sundaramoorthi
Raji
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Thomas
R Mathew
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Liu
Shuangying
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Banda
Geetha
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Lentini
Scott P
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Das
Sasmita
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Xu
Qihong
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Keats
Jeff
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Wang
Frank
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Wardwell
Scott
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Ning
Yaoyu
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Snodgrass
Joseph T
JT
Broudy
Marc I
MI
Russian
Karin
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Daley
George Q
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Iuliucci
John
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Dalgarno
David C
DC
Clackson
Tim
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Sawyer
Tomi K
TK
Shakespeare
William C
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D000818:Animals; D015195:Drug Design; D005260:Female; D006801:Humans; D020014:K562 Cells; D051379:Mice; D041681:NIH 3T3 Cells; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011687:Purines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D047428:Protein Kinase Inhibitors; D011687:Purines; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases