Title |
Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein
|
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Published in |
Bioorganic & Medicinal Chemistry Letters, February 2014
|
DOI | 10.1016/j.bmcl.2014.02.010 |
Pubmed ID | |
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 |
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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