Mcl-1, an anti-apoptotic protein of the Bcl-2 family, is overexpressed in many cancers providing a key survival advantage to these aberrant cells. To combat tumor progression and drug resistance, inhibition of Mcl-1 has been proposed as a suitable strategy for the treatment of certain types of cancer. In this presentation, we will describe the discovery of α-hydroxy phenylacetic acid inhibitors following a structure-based design approach and utilizing the X-ray co-crystal structure of a macrocyclic series of inhibitors bound to Mcl-1 as the starting point of this effort. This work culminated with the discovery of a potent Mcl-1 inhibitor with good pharmacokinetic properties and <i>in vivo</i> efficacy in an OPM-2 multiple myeloma xenograft model.

Discovery of a potent and efficacious Mcl-1 inhibitor featuring an α-hydroxy phenylacetic acid pharmacophore

255th National Meeting (2018)

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