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
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AUTHORS (21)
JM
Jesús R. Medina
XT
Xinrong Tian
WL
William H. Li
DS
Dominic Suarez
JM
James F. Mack
LL
Louis LaFrance
CM
Cuthbert Martyr
JB
James Brackley
CD
Christina Di Marco
RR
Ralph Rivero
DH
Dirk A. Heerding
CM
Charles McHugh
EM
Elisabeth Minthorn
AB
Aishwarya Bhaskar
JR
Jacob Rubin
MB
Michael Butticello
CC
Christopher Carpenter
EN
Eldridge N. Nartey
TB
Thomas J. Berrodin
LK
Lorena A. Kallal
KEYWORDS
screening effort designedrapidly decrease endogenousmodulate pharmacokinetics propertiesmedicinal chemistry programlike molecule duecells elevated expressionbased approach usedtarget myc indirectlydisrupt myc functiondirectly target mycidentify pharmacological inhibitors>- myc oncogene>- myc knockdownbased drug discovery>- mycmyc -identify compoundsyet yieldedsmall moleculesreducing compoundsrecently describedorally bioavailablehuman cancerscompound seriescommon abnormalitiesc