Structure-Activity Relationships of Cbx7 Inhibitors, Including Selectivity Studies against Other Cbx Proteins

ACS Omega
Chakravarthi SimhadriFraser Hof

Abstract

The five human polycomb (Pc) paralog proteins, chromobox homolog (Cbx) 2/4/6/7/8, are a family of chromodomain containing methyllysine reader proteins that are canonical readers of trimethyllysine 27 on histone 3 (H3K27me3). The aberrant expression of the Cbx7 gene is implicated in several cancers including prostate, gastric, thyroid, pancreas, and colon cancer. Previous reports on antagonizing the molecular recognition of Cbx7-H3K27me3 with chemical inhibitors showed an impact on prostate cancer cell lines. We report here on the design, synthesis, and structure-activity relationships of a series of potent peptidomimetic antagonists that were optimized on a trimethyllysine-containing scaffold to target Cbx7. The ligands were characterized using fluorescence polarization (FP) for their binding efficiency and selectivity against the Pc paralog Cbx proteins. The most selective ligand 9, as indicated by the FP data analysis, was further characterized using the isothermal titration calorimetry (ITC). Compound 9 exhibits a 220 nM potency for Cbx7 and exhibits 3.3, 1.8, 7.3 times selective for Cbx7 over Cbx2/4/8 and 28-fold selective over the HP1 family member Cbx1. Our research provides several potent and partially selective inhibito...Continue Reading

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Citations

Jun 11, 2019·Expert Opinion on Therapeutic Targets·Maïka JangalMichael Witcher
Jun 30, 2019·ChemMedChem·Chakravarthi SimhadriFraser Hof
Feb 22, 2017·Journal of Peptide Science : an Official Publication of the European Peptide Society·Mariam TraoréWilliam D Lubell
Jun 27, 2021·ChemMedChem·Natalia MilosevichFraser Hof

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Methods Mentioned

BETA
glycosylation
isothermal titration calorimetry
X-ray
Fluorescence

Software Mentioned

Excel
PyMOL
Origin
XLFit
MOLOC

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