Highly Ligand Efficient and Selective N‐2‐(Thioethyl)picolinamide Histone Deacetylase Inhibitors Inspired by the Natural Product Psammaplin A |
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Authors: | Matthias G J Baud Patricia Haus Thomas Leiser Prof?Dr Franz‐Josef Meyer‐Almes Dr Matthew J Fuchter |
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Affiliation: | 1. Department of Chemistry, Imperial College London, London SW7?2AZ (UK);2. Department of Chemical Engineering and Biotechnology, University of Applied Sciences Darmstadt, Schnittspahnstra?e 12, 64287 Darmstadt (Germany) |
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Abstract: | Novel picolinamide‐based histone deacetylase (HDAC) inhibitors were developed, drawing inspiration from the natural product psammaplin A. We found that the HDAC potency and isoform selectivity provided by the oxime unit of psammaplin A could be reproduced by using carefully chosen heterocyclic frameworks. The resulting (hetero)aromatic amide based compounds displayed very high potency and isoform selectivity among the HDAC family, in addition to excellent ligand efficiency relative to previously reported HDAC inhibitors. In particular, the high HDAC1 isoform selectivity provided by the chloropyridine motif represents a valuable design criterion for the development of new lead compounds and chemical probes that target HDAC1. |
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Keywords: | epigenetics HDAC inhibitors isoform selectivity ligand design psammaplin A |
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