- Rational Adaptation of L3MBTL1 Inhibitors to Create Small-Molecule Cbx7 Antagonists
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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 μm) potency.
- Simhadri, Chakravarthi,Daze, Kevin D.,Douglas, Sarah F.,Milosevich, Natalia,Monjas, Leticia,Dev, Amarjot,Brown, Tyler M.,Hirsch, Anna K. H.,Wulff, Jeremy E.,Hof, Fraser
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supporting information
p. 1444 - 1456
(2019/08/02)
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- Biophysical probes reveal a "compromise" Nature of the Methyl-lysine Binding Pocket in L3MBTL1
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Histone lysine methylation (Kme) encodes essential information modulating many biological processes including gene expression and transcriptional regulation. However, the atomic-level recognition mechanisms of methylated histones by their respective adaptor proteins are still elusive. For instance, it is unclear how L3MBTL1, a methyl-lysine histone code reader, recognizes equally well both mono- and dimethyl marks but ignores unmodified and trimethylated lysine residues. We made use of molecular dynamics (MD) and free energy perturbation (FEP) techniques in order to investigate the energetics and dynamics of the methyl-lysine recognition. Isothermal titration calorimetry (ITC) was employed to experimentally validate the computational findings. Both computational and experimental methods were applied to a set of designed "biophysical" probes that mimic the shape of a single lysine residue and reproduce the binding affinities of cognate histone peptides. Our results suggest that, besides forming favorable interactions, the L3MBTL1 binding pocket energetically penalizes both methylation states and has most probably evolved as a "compromise" that nonoptimally fits to both mono- and dimethyl-lysine marks.(Figure Presented)
- Gao, Cen,Herold, J. Martin,Kireev, Dmitri,Wigle, Tim,Norris, Jacqueline L.,Frye, Stephen
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supporting information; experimental part
p. 5357 - 5362
(2011/06/11)
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- Development and characterization of biphenylsulfonamides as novel inhibitors of bone resorption
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Increased osteoclastic bone resorption plays a central role in the pathogenesis of many bone diseases, and osteoclast inhibitors are the most widely used treatments for these diseases. We have identified and characterized a series of novel biphenylsulfona
- Greig, Iain R.,Idris, Aymen I.,Ralston, Stuart H.,Van't Hof, Rob J.
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p. 7487 - 7492
(2007/10/03)
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