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

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.