Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency.

Autor: Farand J; Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: Julie.Farand@gilead.com., Mai N; Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA., Chandrasekhar J; Department of Structural Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA., Newby ZE; Department of Structural Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA., Van Veldhuizen J; Department of Medicinal Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA., Loyer-Drew J; Department of Medicinal Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA., Venkataramani C; Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA., Guerrero J; Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA., Kwok A; Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA., Li N; Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA., Zherebina Y; Department of Biology, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA., Wilbert S; Department of Drug Metabolism, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA., Zablocki J; Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA., Phillips G; Department of Medicinal Chemistry, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA., Watkins WJ; Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA., Mourey R; Department of Biology, Gilead Sciences, Inc., 199 East Blaine Street, Seattle, WA 98102, USA., Notte GT; Department of Medicinal Chemistry, Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Dec 15; Vol. 26 (24), pp. 5926-5930. Date of Electronic Publication: 2016 Nov 02.
DOI: 10.1016/j.bmcl.2016.10.092
Abstrakt: Herein, we describe the synthesis of Pyk2 inhibitors via macrocyclization of FAK and dual Pyk2-FAK inhibitors. We identified macrocycle 25a as a highly potent Pyk2 inhibitor (IC 50 =0.7nM), with ∼175-fold improvement in Pyk2 potency as compared to its acyclic counterpart. In many cases, macrocyclization improved Pyk2 potency while weakening FAK potency, thereby improving the Pyk2/FAK selectivity ratio for this structural class of inhibitors. Various macrocyclic linkers were studied in an attempt to optimize Pyk2 selectivity. We observed macrocyclic atropisomerism during the synthesis of 19-membered macrocycles 10a-d, and successfully obtained crystallographic evidence of one atropisomer (10a-AtropB) preferentially bound to Pyk2.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: