Rational Adaptation of L3MBTL1 Inhibitors to Create Small-Molecule Cbx7 Antagonists.
| Autor: | Simhadri C; Department of Chemistry, University of Victoria, Victoria, BC, V8P 5C2, Canada., Daze KD; Department of Chemistry, University of Victoria, Victoria, BC, V8P 5C2, Canada., Douglas SF; Department of Chemistry, University of Victoria, Victoria, BC, V8P 5C2, Canada., Milosevich N; Department of Chemistry, University of Victoria, Victoria, BC, V8P 5C2, Canada., Monjas L; Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands., Dev A; Department of Chemistry, University of Victoria, Victoria, BC, V8P 5C2, Canada., Brown TM; Department of Chemistry, University of Victoria, Victoria, BC, V8P 5C2, Canada., Hirsch AKH; Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.; Present affiliation: Department for Drug Design and Optimization and Department of Pharmacy, Helmholtz Institute for Pharmaceutical Research (HIPS)-Helmholtz Centre for Infection Research (HZI), Saarland University, Campus Building E 8.1, 66123, Saarbrücken, Germany., Wulff JE; Department of Chemistry, University of Victoria, Victoria, BC, V8P 5C2, Canada., Hof F; Department of Chemistry, University of Victoria, Victoria, BC, V8P 5C2, Canada. |
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| Jazyk: | angličtina |
| Zdroj: | ChemMedChem [ChemMedChem] 2019 Aug 06; Vol. 14 (15), pp. 1444-1456. Date of Electronic Publication: 2019 Jul 22. |
| DOI: | 10.1002/cmdc.201900021 |
| Abstrakt: | 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 (IC (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.) |
| Databáze: | MEDLINE |
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