Skip to main content

Fesik Lab

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

AUTHORS

Lee TTaekyu , Bian ZZhiguo , Zhao BBin , Hogdal LJLeah J , Sensintaffar JLJohn L , Goodwin CMCraig M , Belmar JJohannes , Shaw SSubrata , Tarr JCJames C , Veerasamy NNagarathanam , Matulis SMShannon M , Koss BBrian , Fischer MAMelissa A , Arnold ALAllison L , Camper DVDeMarco V , Browning CFCarrie F , Rossanese OWOlivia W , Budhraja AAmit , Opferman JJoseph , Boise LHLawrence H , Savona MRMichael R , Letai AAnthony , Olejniczak ETEdward T , Fesik SWStephen 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.