Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
10586930 | Bioorganic & Medicinal Chemistry Letters | 2014 | 5 Pages |
Abstract
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.
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Authors
Andrew M. Petros, Steven L. Swann, Danying Song, Kerren Swinger, Chang Park, Haichao Zhang, Michael D. Wendt, Aaron R. Kunzer, Andrew J. Souers, Chaohong Sun,