Overexpression of the anti-apoptotic proteins of the BCL-2 family, specifically Bcl-2, Bcl-xL and Mcl-1, leads to tumorigenesis through the sequestration of neutralization of their pro-apoptotic counterparts through their BH3 α-helical “death” domains. Likewise, MDM2 and MDMX sequester and inhibit the tumor suppressor p53 through its α-helical transactivation domain. It is noteworthy that both members of the BCL-2 and MDM2 families are co-upregulated in many cancers, including acute myeloid leukemia. Significantly, the recognition patterns presented by the hydrophobic faces of both the BH3 and p53 α-helical domains are similar; Bak-BH3: Leu62, Ile65 and Phe69; p53: Phe19, Trp23 and Leu26. On the opposing faces, there are conserved aspartates between the i and i+4 residues; while this plays a functional role in the BH3 α-helices in the recognition of their target proteins, its role in the p53 α-helix is only to ensure proper folding into the secondary structure. Therefore, towards more efficacious anti-cancer agents, we have designed small-molecule α-helix mimetics based on heterocyclic scaffolds to co-emulate both faces of the BH3 and p53 α-helices. Preliminary evaluations have validated our polypharmacology design rationale, and we will present an investigation into the structure–activity relationships of our novel α-helix mimetics across the BCL-2 and MDM2 families of proteins.

Two-faced synthetic α-helix mimetics based on heterocyclic cores as dual BCL-2/MDM2 inhibitors

253rd National Meeting (2017)

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