Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK)

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• 作者：Gregory R. Ott ; Mangeng Cheng ; Keith S. Learn ; Jason Wagner ; Diane E. Gingrich ; Joseph G. Lisko ; Matthew Curry ; Eugen F. Mesaros ; Arup K. Ghose ; Matthew R. Quail ; Weihua Wan ; Lihui Lu ; Pawel Dobrzanski ; Mark S. Albom ; Thelma S. Angeles ; Kevin Wells-Knecht ; Zeqi Huang ; Lisa D. Aimone ; Elizabeth Bruckheimer ; Nathan Anderson ; Jay Friedman ; Sandra V. Fernandez ; Mark A. Ator ; Bruce A. Ruggeri ; Bruce D. Dorsey
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：August 25, 2016
• 年：2016
• 卷：59
• 期：16
• 页码：7478-7496
• 全文大小：935K
• 年卷期：0
• ISSN：1520-4804

文摘

Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.