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

Authors

Burke JP Jason P , Bian Z Zhiguo , Shaw S Subrata , Zhao B Bin , Goodwin CM Craig M , Belmar J Johannes , Browning CF Carrie F , Vigil D Dominico , Friberg A Anders , Camper DV DeMarco V , Rossanese OW Olivia W , Lee T Taekyu , Olejniczak ET Edward T , Fesik SW Stephen 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.