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

Abstract

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.

DOI: 10.1021/acs.jmedchem.6b00487

Cite this paper

@article{Ott2016DiscoveryOC, title={Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK).}, author={Gregory R. Ott and Mangeng Cheng and Keith S Learn and Jason C Wagner and Diane E. Gingrich and Joseph G Lisko and Matthew A Curry and Eugen F Mesaros and Arup K. Ghose and Matthew R. Quail and Weihua Wan and Lihui Lu and Pawel Dobrzanski and Mark S. Albom and Thelma S. Angeles and Kevin J Wells-Knecht and Zeqi Huang and Lisa D. Aimone and Elizabeth Bruckheimer and Nathan Thomas Anderson and Jay A Friedman and Sandra Fernandez and Mark A. Ator and Bruce A. Ruggeri and Bruce D. Dorsey}, journal={Journal of medicinal chemistry}, year={2016}, volume={59 16}, pages={7478-96} }