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

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• 作者：Julie Farand^a ; ^{Julie.Farand@gilead.com} ; Nicholas Mai^a ; Jayaraman Chandrasekhar^e ; Zachary E. Newby^b ; Josh Van Veldhuizen^d ; Jennifer Loyer-Drew^d ; Chandrasekar Venkataramani^a ; Juan Guerrero^a ; Amy Kwok^c ; Ning Li^c ; Yelena Zherebina^c ; Sibylle Wilbert^f ; Jeff Zablocki^a ; Gary Phillips^d ; William J. Watkins^a ; Robert Mourey^g ; Gregory T. Notte^a
• 关键词：Pyk2 ; FAK ; Macrocycle ; Atropisomer ; Glioblastoma
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 December 2016
• 年：2016
• 卷：26
• 期：24
• 页码：5926-5930
• 全文大小：1370 K
• 卷排序：26

文摘

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 = 0.7 nM), 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.