Mcl-1 is an anti-apoptotic member of the Bcl-2 family of proteins which act via protein–protein interactions between pro- and anti-apoptotic factions to mediate the intrinsic pathway of programmed cell death. Identification of Mcl-1 as a key pro-survival factor in many human cancers and its association with tumor progression and resistance to chemotherapy has made it a highly desirable drug target. Although compelling, targeting disruption of Mcl-1’s protein–protein interaction to induce tumor cell death, was previously thought to be “un-druggable,” due to the high affinities of Mcl-1 to the pro-apoptotic Bcl-2 proteins and lack of a small molecule binding pocket. This presentation will describe the convergence of structural information and small molecule conformational analysis applied to the optimization of a small molecule high-throughput screening hit culminating in the identification of the Mcl-1 inhibitor AMG 176. A phase 1 clinical trial is currently evaluating AMG 176 in multiple myeloma patients.

Interdiction at a protein-protein interface: Structure-based design of the Mcl-1 inhibitor AMG 176

255th National Meeting (2018)

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