Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 21, Pages 16056-16087Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01416
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The study identified an indirect strategy to target c-MYC and successfully discovered a series of compounds with c-MYC reducing effects. Through the medicinal chemistry program, the research team identified orally bioavailable potent c-MYC-reducing compounds. The study also developed a minimum pharmacophore model and a property-based approach to modulate pharmacokinetics properties.
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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