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Cell-Based Drug Discovery: Identification and Optimization of Small Molecules that Reduce c-MYC Protein Levels in Cells
Journal of Medicinal Chemistry  (IF7.446),  Pub Date : 2021-10-20, DOI: 10.1021/acs.jmedchem.1c01416
Jesús R. Medina, Xinrong Tian, William H. Li, Dominic Suarez, James F. Mack, Louis LaFrance, Cuthbert Martyr, James Brackley, Christina Di Marco, Ralph Rivero, Dirk A. Heerding, Charles McHugh, Elisabeth Minthorn, Aishwarya Bhaskar, Jacob Rubin, Michael Butticello, Christopher Carpenter, Eldridge N. Nartey, Thomas J. Berrodin, Lorena A. Kallal, Biju Mangatt

Elevated expression of the c-MYC oncogene is one of the most common abnormalities in human cancers. Unfortunately, efforts to identify pharmacological inhibitors that directly target MYC have not yet yielded a drug-like molecule due to the lack of any known small molecule binding pocket in the protein, which could be exploited to disrupt MYC function. We have recently described a strategy to target MYC indirectly, where a screening effort designed to identify compounds that can rapidly decrease endogenous c-MYC protein levels in a MYC-amplified cell line led to the discovery of a compound series that phenocopies c-MYC knockdown by siRNA. Herein, we describe our medicinal chemistry program that led to the discovery of potent, orally bioavailable c-MYC-reducing compounds. The development of a minimum pharmacophore model based on empirical structure activity relationship as well as the property-based approach used to modulate pharmacokinetics properties will be highlighted.