Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency.
Basic Information
ID: ALA3872238
Journal: Bioorg Med Chem Lett
Title: Selectivity switch between FAK and Pyk2: Macrocyclization of FAK inhibitors improves Pyk2 potency.
Authors: Farand J, Mai N, Chandrasekhar J, Newby ZE, Van Veldhuizen J, Loyer-Drew J, Venkataramani C, Guerrero J, Kwok A, Li N, Zherebina Y, Wilbert S, Zablocki J, Phillips G, Watkins WJ, Mourey R, Notte GT.
Abstract: 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 (IC50=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.
CiteXplore: 27876318
DOI: 10.1016/j.bmcl.2016.10.092
Patent ID: ┄