Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design
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.
Burke, Jason P.,Bian, Zhiguo,Shaw, Subrata,Zhao, Bin,Goodwin, Craig M.,Belmar, Johannes,Browning, Carrie F.,Vigil, Dominico,Friberg, Anders,Camper, DeMarco V.,Rossanese, Olivia W.,Lee, Taekyu,Olejniczak, Edward T.,Fesik, Stephen W.
p. 3794 - 3805
(2015/05/27)
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