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Fesik Lab

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

AUTHORS

Pelz NFNicholas F , Bian ZZhiguo , Zhao BBin , Shaw SSubrata , Tarr JCJames C , Belmar JJohannes , Gregg CClaire , Camper DVDeMarco V , Goodwin CMCraig M , Arnold ALAllison L , Sensintaffar JLJohn L , Friberg AAnders , Rossanese OWOlivia W , Lee TTaekyu , Olejniczak ETEdward T , Fesik SWStephen 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.