Discovery of an Orally Efficacious Inhibitor of Anaplastic Lymphoma Kinase

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• 作者：Diane E. Gingrich ; Joseph G. Lisko ; Matthew A. Curry ; Mangeng Cheng ; Matthew Quail ; Lihui Lu ; Weihua Wan ; Mark S. Albom ; Thelma S. Angeles ; Lisa D. Aimone ; R. Curtis Haltiwanger ; Kevin Wells-Knecht ; Gregory R. Ott ; Arup K. Ghose ; Mark A. Ator ; Bruce Ruggeri ; Bruce D. Dorsey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：May 24, 2012
• 年：2012
• 卷：55
• 期：10
• 页码：4580-4593
• 全文大小：476K
• 年卷期：v.55,no.10(May 24, 2012)
• ISSN：1520-4804

文摘

Anaplastic lymphoma kinase (ALK) is a promising therapeutic target for the treatment of cancer, supported by considerable favorable preclinical and clinical activities over the past several years and culminating in the recent FDA approval of the ALK inhibitor crizotinib. Through a series of targeted modifications on an ALK inhibitor diaminopyrimidine scaffold, our research group has driven improvements in ALK potency, kinase selectivity, and overall pharmaceutical properties. Optimization of this scaffold has led to the identification of a potent and efficacious inhibitor of ALK, 25b. A striking feature of 25b over previously described ALK inhibitors is its >600-fold selectivity over insulin receptor (IR), a closely related kinase family member. Most importantly, 25b exhibited dose proportional escalation in rat compared to compound 3 which suffered dose limiting absorption preventing further advancement. Compound 25b exhibited significant in vivo antitumor efficacy when dosed orally in an ALK-positive ALCL tumor xenograft model in SCID mice, warranting further assessment in advanced preclinical models.