Rationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2.

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TitleRationally Designed Polypharmacology: α-Helix Mimetics as Dual Inhibitors of the Oncoproteins Mcl-1 and HDM2.
Publication TypeJournal Article
Year of Publication2020
AuthorsConlon, IL, Drennen, B, Lanning, ME, Hughes, S, Rothhaas, R, Wilder, PT, Mackerell, AD, Fletcher, S
JournalChemMedChem
Date Published2020 Jun 25
ISSN1860-7187
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.

DOI10.1002/cmdc.202000278
Alternate JournalChemMedChem
PubMed ID32583936
Grant ListT32GM066706 / NH / NIH HHS / United States
/ / University of Maryland School of Pharmacy /