Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods.

Authors

Pelz NF Nicholas F , Bian Z Zhiguo , Zhao B Bin , Shaw S Subrata , Tarr JC James C , Belmar J Johannes , Gregg C Claire , Camper DV DeMarco V , Goodwin CM Craig M , Arnold AL Allison L , Sensintaffar JL John L , Friberg A Anders , Rossanese OW Olivia W , Lee T Taekyu , Olejniczak ET Edward T , Fesik SW Stephen W .
Journal of medicinal chemistry. 2016 3 10; 59(5).
2054-66

Abstract

Myeloid cell leukemia-1 (Mcl-1) is a member of the Bcl-2 family of proteins responsible for the regulation of programmed cell death. Amplification of Mcl-1 is a common genetic aberration in human cancer whose overexpression contributes to the evasion of apoptosis and is one of the major resistance mechanisms for many chemotherapies. Mcl-1 mediates its effects primarily through interactions with pro-apoptotic BH3 containing proteins that achieve high affinity for the target by utilizing four hydrophobic pockets in its binding groove. Here we describe the discovery of Mcl-1 inhibitors using fragment-based methods and structure-based design. These novel inhibitors exhibit low nanomolar binding affinities to Mcl-1 and >500-fold selectivity over Bcl-xL. X-ray structures of lead Mcl-1 inhibitors when complexed to Mcl-1 provided detailed information on how these small-molecules bind to the target and were used extensively to guide compound optimization.