Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein

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• 作者：Andrew M. Petros ; ^{andrew.petros@abbvie.com" class="auth_mail} ; Steven L. Swann ; Danying Song ; Kerren Swinger ; Chang Park ; Haichao Zhang ; Michael D. Wendt ; Aaron R. Kunzer ; Andrew J. Souers ; Chaohong Sun ; ^{chaohong.sun@abbvie.com" class="auth_mail}
• 关键词：NMR ; Fragment-based ; FBDD ; FBLD ; Apoptosis ; BCL ; MCL-1
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：15 March, 2014
• 年：2014
• 卷：24
• 期：6
• 页码：1484-1488
• 全文大小：5088 K

文摘

Apoptosis is regulated by the BCL-2 family of proteins, which is comprised of both pro-death and pro-survival members. Evasion of apoptosis is a hallmark of malignant cells. One way in which cancer cells achieve this evasion is thru overexpression of the pro-survival members of the BCL-2 family. Overexpression of MCL-1, a pro-survival protein, has been shown to be a resistance factor for Navitoclax, a potent inhibitor of BCL-2 and BCL-XL. Here we describe the use of fragment screening methods and structural biology to drive the discovery of novel MCL-1 inhibitors from two distinct structural classes. Specifically, cores derived from a biphenyl sulfonamide and salicylic acid were uncovered in an NMR-based fragment screen and elaborated using high throughput analog synthesis. This culminated in the discovery of selective and potent inhibitors of MCL-1 that may serve as promising leads for medicinal chemistry optimization efforts.