- Early Drug-Discovery Efforts towards the Identification of EP300/CBP Histone Acetyltransferase (HAT) Inhibitors
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EP300 and CBP (KAT3A/3B) are two highly homologous, multidomain, epigenetic coregulators that play central roles in transcription through the acetylation of lysine residues on histones and other proteins. Both enzymes have been implicated in human diseases, especially cancer. From a high-throughput screen of 191 000 compounds searching for EP300/CBP histone acetyltransferase (HAT) inhibitors, 18 compounds were characterized by a suite of biochemical enzymatic assays and biophysical methods, including X-ray crystallography and native mass spectrometry. This work resulted in the discovery of three distinct mechanistic classes of EP300/CBP HAT inhibitors, including two classes not previously described. The profiles of an example of each class of inhibitor are described in detail. A subsequent medicinal chemistry effort led to the development of a novel class of orally bioavailable AcCoA-competitive EP300/CBP HAT inhibitors with in vivo activity. We believe that this work will prove to be a useful guide for other groups interested in the development of HAT inhibitors.
- Audia, James E.,Bommi-Reddy, Archana,Brucelle, Francois,Cantone, Nico,Cummings, Richard,Gardberg, Anna S.,Huhn, Annissa J.,Levell, Julian,Patel, Chirag,Patel, Gaurav,Poy, Florence,Sims, Robert,Vivat, Valerie,Wilson, Jonathan E.
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- Light-Enabled Enantiodivergence: Stereospecific Reduction of Activated Alkenes Using a Single Organocatalyst Enantiomer
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Light-enabled enantiodivergence is demonstrated in which the alkene substrate configuration is manipulated (E → Z) prior to organocatalytic reduction with a chiral thiourea and Hantzsch ester. This allows stereodivergent reduction to be regulated at the substrate level with high fidelity and mitigates the need for a second, enantiomeric catalyst (up to 93:07 and 95:5 er). The synthetic utility of this strategy has been demonstrated in the synthesis of the weight-loss drug (R)-Lorcaserin (Belviq) and a potent AMPA modulator.
- Hostmann, Theresa,Molloy, John J.,Bussmann, Kathrin,Gilmour, Ryan
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p. 10164 - 10168
(2019/12/24)
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- NEW COMPOUNDS I/418
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There is provided compounds of formula I, wherein R1 to R7 have meanings given in the description, which are useful in the prophylaxis and in the treatment of arrhythmias, in particular atrial and ventricular arrhythmias.
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Page/Page column 28
(2008/06/13)
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- Efficient Cu-catalyzed asymmetric conjugate additions of alkylzinc reagents to aromatic and aliphatic acyclic nitroalkenes
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An efficient and highly enantioselective (up to 95% ee) Cu-catalyzed method for asymmetric conjugate addition (ACA) of alkylzinc reagents to acyclic disubstituted nitroalkenes is presented. Reactions are typically effected at ambient temperature in the presence of 2 mol % chiral dipeptide phosphine and 1 mol % (CuOTf)2·C6H6. Nitroalkenes bearing aromatic as well as aliphatic substituents readily undergo asymmetric additions.
- Mampreian, Dawn M.,Hoveyda, Amir H.
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p. 2829 - 2832
(2007/10/03)
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- Asymmetric Hydrogenation of 2-Aryl-1-nitropropenes by Fermenting Bakers'Yeast
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2-Aryl-1-nitropropenes were enantioselectively hydrogenated on C=C double bonds by incubation with fermenting bakers' yeast to afford optically active 2-aryl-1-nitopropanes.
- Ohta, Hiromichi,Ozaki, Kazuhiko,Tsuchihashi, Gen-ichi
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p. 191 - 192
(2007/10/02)
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