117273-45-7Relevant academic research and scientific papers
Discovery of tricyclic indoles that potently inhibit Mcl-1 using fragment-based methods and structure-based design
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)
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.
