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

Autor:	Nathan Anderson, Diane E. Gingrich, Arup K. Ghose, Mark S. Albom, Bruce D. Dorsey, Lisa D. Aimone, Elizabeth Bruckheimer, Jason C. Wagner, Matthew A. Curry, Lihui Lu, Jay Friedman, Mark A. Ator, Bruce Ruggeri, Eugen F. Mesaros, Mangeng Cheng, Zeqi Huang, Keith S. Learn, Matthew R. Quail, Thelma S. Angeles, Pawel Dobrzanski, Gregory R. Ott, Sandra V. Fernandez, Joseph G. Lisko, Kevin J. Wells-Knecht, Weihua Wan
Rok vydání:	2016
Předmět:	0301 basic medicine Models Molecular medicine.drug_class Administration Oral Mice Nude Mice SCID Metastasis Focal adhesion 03 medical and health sciences Mice Structure-Activity Relationship 0302 clinical medicine In vivo hemic and lymphatic diseases Cell Line Tumor Drug Discovery medicine Anaplastic lymphoma kinase Animals Humans Anaplastic Lymphoma Kinase Protein Kinase Inhibitors Cell Proliferation Dose-Response Relationship Drug Molecular Structure Cell growth Chemistry Drug discovery Receptor Protein-Tyrosine Kinases Neoplasms Experimental medicine.disease In vitro ALK inhibitor Benzocycloheptenes 030104 developmental biology Biochemistry 030220 oncology & carcinogenesis Focal Adhesion Kinase 1 Benzamides Cancer research Molecular Medicine Female Drug Screening Assays Antitumor
Zdroj:	Journal of medicinal chemistry. 59(16)
ISSN:	1520-4804
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2f38d2d8693c2496a71a1241c7558ff6 https://pubmed.ncbi.nlm.nih.gov/27527804 Zobrazit plný text záznamu