1580483-83-5Relevant articles and documents
Fragment-based discovery of potent inhibitors of the anti-apoptotic MCL-1 protein
Petros, Andrew M.,Swann, Steven L.,Song, Danying,Swinger, Kerren,Park, Chang,Zhang, Haichao,Wendt, Michael D.,Kunzer, Aaron R.,Souers, Andrew J.,Sun, Chaohong
, p. 1484 - 1488 (2014/03/21)
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.
