Bcl-xL and Mcl-1 are anti-apoptotic proteins of the B-cell lymphoma (Bcl-2) family localized in the outer mitochondrial membrane that are over-expressed in a wide range of human cancers, and contribute to resistance to conventional chemotherapy drugs. These proteins exert their anti-apoptotic functions through sequestering pro-apoptotic Bcl-2 family members, which include Bak and Bim. More particularly, this protein�protein interaction is mediated by a hydrophobic groove on the surface of the anti-apoptotic protein and the BH3 a�helix of the pro-apoptotic protein. Although small-molecule mimicry of the BH3 a�helix has afforded potent Bcl-xL inhibitors, the likewise inhibition of Mcl-1 has not been forthcoming. Thus, in an effort to develop potent and selective Mcl-1 inhibitors, as well as pan-Bcl-2 inhibitors, we have translated the recent findings of saturation mutagenesis studies of the Bim-BH3 a�helix into our synthetic a�helix mimetics, and we will present the outcomes of our research.

Towards selective Mcl-1 and pan-Bcl-2 antagonists: Structure–activity relationships of side-chain substitutions of synthetic α–helix mimetics

245th National Meeting (2013)

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