Discovery and biological characterization of potent myeloid cell leukemia-1 inhibitors.

Authors

Lee T Taekyu , Bian Z Zhiguo , Zhao B Bin , Hogdal LJ Leah J , Sensintaffar JL John L , Goodwin CM Craig M , Belmar J Johannes , Shaw S Subrata , Tarr JC James C , Veerasamy N Nagarathanam , Matulis SM Shannon M , Koss B Brian , Fischer MA Melissa A , Arnold AL Allison L , Camper DV DeMarco V , Browning CF Carrie F , Rossanese OW Olivia W , Budhraja A Amit , Opferman J Joseph , Boise LH Lawrence H , Savona MR Michael R , Letai A Anthony , Olejniczak ET Edward T , Fesik SW Stephen W .
FEBS letters. 2017 1 ; 591(1).
240-251

Abstract

Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic member of the Bcl-2 family of proteins that when overexpressed is associated with high tumor grade, poor survival, and resistance to chemotherapy. Mcl-1 is amplified in many human cancers, and knockdown of Mcl-1 using RNAi can lead to apoptosis. Thus, Mcl-1 is a promising cancer target. Here, we describe the discovery of picomolar Mcl-1 inhibitors that cause caspase activation, mitochondrial depolarization, and selective growth inhibition. These compounds represent valuable tools to study the role of Mcl-1 in cancer and serve as useful starting points for the discovery of clinically useful Mcl-1 inhibitors.