1585223-89-7Relevant articles and documents
Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods
Pelz, Nicholas F.,Bian, Zhiguo,Zhao, Bin,Shaw, Subrata,Tarr, James C.,Belmar, Johannes,Gregg, Claire,Camper, DeMarco V.,Goodwin, Craig M.,Arnold, Allison L.,Sensintaffar, John L.,Friberg, Anders,Rossanese, Olivia W.,Lee, Taekyu,Olejniczak, Edward T.,Fesik, Stephen W.
, p. 2054 - 2066 (2016/03/22)
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.
