Cell-Based Drug
Discovery: Identification and Optimization
of Small Molecules that Reduce c‑MYC Protein
Levels in Cells
Posted on 2021-10-20 - 19:36
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.
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Medina, Jesús R.; Tian, Xinrong; Li, William H.; Suarez, Dominic; Mack, James F.; LaFrance, Louis; et al. (2021). Cell-Based Drug
Discovery: Identification and Optimization
of Small Molecules that Reduce c‑MYC Protein
Levels in Cells. ACS Publications. Collection. https://doi.org/10.1021/acs.jmedchem.1c01416