title: 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: ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, Massachusetts 02139, USA. wei-sheng.huang@ariad.com
authors: Wei-Sheng
authors: WS
authors: Huang
authors: Xiaotian
authors: X
authors: Zhu
authors: Yihan
authors: Y
authors: Wang
authors: Mohammad
authors: M
authors: Azam
authors: David
authors: D
authors: Wen
authors: Raji
authors: R
authors: Sundaramoorthi
authors: R Mathew
authors: RM
authors: Thomas
authors: Shuangying
authors: S
authors: Liu
authors: Geetha
authors: G
authors: Banda
authors: Scott P
authors: SP
authors: Lentini
authors: Sasmita
authors: S
authors: Das
authors: Qihong
authors: Q
authors: Xu
authors: Jeff
authors: J
authors: Keats
authors: Frank
authors: F
authors: Wang
authors: Scott
authors: S
authors: Wardwell
authors: Yaoyu
authors: Y
authors: Ning
authors: Joseph T
authors: JT
authors: Snodgrass
authors: Marc I
authors: MI
authors: Broudy
authors: Karin
authors: K
authors: Russian
authors: George Q
authors: GQ
authors: Daley
authors: John
authors: J
authors: Iuliucci
authors: David C
authors: DC
authors: Dalgarno
authors: Tim
authors: T
authors: Clackson
authors: Tomi K
authors: TK
authors: Sawyer
authors: William C
authors: WC
authors: Shakespeare
mesh_terms: 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
chemical_list: D047428:Protein Kinase Inhibitors; D011687:Purines; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases