by
Taekyu Lee;
Zhiguo Bian;
Bin Zhao;
Leah J. Hogdal;
John L. Sensintaffar;
Craig M. Goodwin;
Johannes Belmar;
Subrata Shaw;
James C. Tarr;
Nagarathanam Veerasamy;
Shannon M Matulis;
Brian Koss;
Melissa A. Fischer;
Allison L. Arnold;
DeMarco V. Camper;
Lawrence Boise
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. PDB ID codes: Comp. 2: 5IEZ; Comp. 5: 5IF4.