c-Myc is a nuclear oncoprotein of the basic helix-loop-helix leucine zipper (bHLH-LZ) family that is required for the transcription of genes involved in the regulation of the cell cycle, cell proliferation, differentiation, metabolism and survival. In order for c-Myc to become transcriptionally active, it must first heterodimerize with Max, forming a coiled coil structure. Overexpression and/or dysregulation of c-Myc is responsible for the development and progression of a variety of human cancers. Accordingly, the development of c-Myc inhibitors represents a highly targeted, and now validated, approach towards the expansion of the antineoplastic drug arsenal. Through consideration of the c-Myc�Max/DNA crystal structure, we have designed novel a-helix mimetics intended to perturb the structure of the c-Myc�Max heterodimer through disruption of the helix�helix interface. Our most potent compounds inhibit c-Myc�Max dimerization with single-digit micromolar IC50 values in vitro and in c-Myc-overexpressing cell lines.

Rationally-designed small-molecule inhibitors of c-Myc–Max dimerization

245th National Meeting (2013)

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