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Fesik Lab

Optimization of Potent and Selective Tricyclic Indole Diazepinone Myeloid Cell Leukemia-1 Inhibitors Using Structure-Based Design.

AUTHORS

Shaw SSubrata , Bian ZZhiguo , Zhao BBin , Tarr JCJames C , Veerasamy NNagarathanam , Jeon KOKyu Ok , Belmar JJohannes , Arnold ALAllison L , Fogarty SAStuart A , Perry EEvan , Sensintaffar JLJohn L , Camper DVDeMarco V , Rossanese OWOlivia W , Lee TTaekyu , Olejniczak ETEdward T , Fesik SWStephen W . Journal of medicinal chemistry. 2018 3 22; 61(6). 2410-2421

ABSTRACT

Myeloid cell leukemia 1 (Mcl-1), an antiapoptotic member of the Bcl-2 family of proteins, has emerged as an attractive target for cancer therapy. Mcl-1 upregulation is often found in many human cancers and is associated with high tumor grade, poor survival, and resistance to chemotherapy. Here, we describe a series of potent and selective tricyclic indole diazepinone Mcl-1 inhibitors that were discovered and further optimized using structure-based design. These compounds exhibit picomolar binding affinity and mechanism-based cellular efficacy, including growth inhibition and caspase induction in Mcl-1-sensitive cells. Thus, they represent useful compounds to study the implication of Mcl-1 inhibition in cancer and serve as potentially useful starting points toward the discovery of anti-Mcl-1 therapeutics.