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Rational Adaptation of L3MBTL1 Inhibitors to Create Small-Molecule Cbx7 Antagonists

Simhadri, C., Daze, K. D., Douglas, S. F., Milosevich, N., Monjas, L., Dev, A., Brown, T. M., Hirsch, A. K. H., Wulff, J. E. & Hof, F., 6-Aug-2019, In : ChemMedChem. 14, 15, p. 1444-1456 13 p.

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  • Rational Adaptation of L3MBTL1 Inhibitors to Create Small‐Molecule Cbx7 Antagonists

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DOI

  • Chakravarthi Simhadri
  • Kevin D. Daze
  • Sarah F. Douglas
  • Natalia Milosevich
  • Leticia Monjas
  • Amarjot Dev
  • Tyler M. Brown
  • Anna K. H. Hirsch
  • Jeremy E. Wulff
  • Fraser Hof

Chromobox homolog 7 (Cbx7) is an epigenetic modulator that is an important driver of multiple cancers. It is a methyl reader protein that operates by recognizing and binding to methylated lysine residues on specific partners. Herein we report our efforts to create low-molecular-weight inhibitors of Cbx7 by making rational structural adaptations to inhibitors of a different methyl reader protein, L3MBTL1, inhibitors that had previously been reported to be inactive against Cbx7. We evaluated each new inhibitor for Cbx7 inhibition by fluorescence polarization assay, and also confirmed the binding of selected inhibitors to Cbx7 by saturation-transfer difference NMR spectroscopy. This work identified multiple small-molecule inhibitors with modest (IC50: 257-500 mu m) potency.

Original languageEnglish
Pages (from-to)1444-1456
Number of pages13
JournalChemMedChem
Volume14
Issue number15
Publication statusPublished - 6-Aug-2019

    Keywords

  • anticancer agents, bromodomains, chromatin, epigenetics, histones, METHYL-LYSINE BINDING, PEPTIDOMIMETIC LIGANDS, READER PROTEIN, CHEMICAL PROBE, NONCODING RNA, POLYCOMB, EXPRESSION, DISCOVERY, POCKET, IDENTIFICATION

ID: 118432065