Rationally Designed Polypharmacology: α‐Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl‐1 and HDM2. (25th June 2020) - Conlon, Ivie L.
Abstract: Protein–protein interactions (PPIs), many of which are dominated by α‐helical recognition domains, play key roles in many essential cellular processes, and the dysregulation of these interactions can cause detrimental effects. For instance, aberrant PPIs involving the Bcl‐2 protein family can lead to several diseases including cancer, neurodegenerative diseases, and diabetes. Interactions between Bcl‐2 pro‐life proteins, such as Mcl‐1, and pro‐death proteins, such as Bim, regulate the intrinsic pathway of apoptosis. p53, a tumor‐suppressor protein, also has a pivotal role in apoptosis and is negatively regulated by its E3 ubiquitin ligase HDM2. Both Mcl‐1 and HDM2 are upregulated in numerous cancers, and, interestingly, there is crosstalk between both protein pathways. Recently, synergy has been observed between Mcl‐1 and HDM2 inhibitors. Towards the development of new anticancer drugs, we herein describe a polypharmacology approach for the dual inhibition of Mcl‐1 and HDM2 by employing three densely functionalized isoxazoles, pyrazoles, and thiazoles as mimetics of key α‐helical domains of their partner proteins. Abstract : The anti‐apoptotic protein Mcl‐1 and E3 ubiquitin ligase HDM2 are both frequently upregulated in cancer. A small‐molecule inhibitor can be developed by mimicking their protein binding partners, Bim and p53, to restore apoptosis in oncogenic cells. Through a polypharmacology approach, we have developed small‐molecule α‐helix mimetics with isoxazole, pyrazole, and thiazole scaffolds that function as dual inhibitors of Mcl‐1 and HDM2.