Cell-Based Drug Discovery: Identification and Optimization of Small Molecules that Reduce c-MYC Protein Levels in Cells PMID: 34669409

ADC Targets in Oncology

2026-04-10

Cell-Based Drug Discovery: Identification and Optimization of Small Molecules that Reduce c-MYC Protein Levels in Cells

J Med Chem. 2021 Nov 11;64(21):16056-16087. doi: 10.1021/acs.jmedchem.1c01416.

Jesús R Medina ¹ , Xinrong Tian ¹ , William H Li ¹ , Dominic Suarez ¹ , James F Mack ¹ , Louis LaFrance ¹ , Cuthbert Martyr ¹ , James Brackley ¹ , Christina Di Marco ¹ , Ralph Rivero ¹ , Dirk A Heerding ¹ , Charles McHugh ² , Elisabeth Minthorn ² , Aishwarya Bhaskar ² , Jacob Rubin ² , Michael Butticello ² , Christopher Carpenter ² , Eldridge N Nartey ¹ , Thomas J Berrodin ² , Lorena A Kallal ¹ , Biju Mangatt ²

Affiliations

Abstract

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.