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Fesik Lab

Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design.

AUTHORS

Burke JPJason P , Bian ZZhiguo , Shaw SSubrata , Zhao BBin , Goodwin CMCraig M , Belmar JJohannes , Browning CFCarrie F , Vigil DDominico , Friberg AAnders , Camper DVDeMarco V , Rossanese OWOlivia W , Lee TTaekyu , Olejniczak ETEdward T , Fesik SWStephen W . Journal of medicinal chemistry. 2015 5 14; 58(9). 3794-805

ABSTRACT

Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that is overexpressed and amplified in many cancers. Overexpression of Mcl-1 allows cancer cells to evade apoptosis and contributes to the resistance of cancer cells to be effectively treated with various chemotherapies. From an NMR-based screen of a large fragment library, several distinct chemical scaffolds that bind to Mcl-1 were discovered. Here, we describe the discovery of potent tricyclic 2-indole carboxylic acid inhibitors that exhibit single digit nanomolar binding affinity to Mcl-1 and greater than 1700-fold selectivity over Bcl-xL and greater than 100-fold selectivity over Bcl-2. X-ray structures of these compounds when complexed to Mcl-1 provide detailed information on how these small-molecules bind to the target, which was used to guide compound optimization.