1. Expanding the HDAC druggable landscape beyond enzymatic activity
- Author
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Julien Olivet, Soon Gang Choi, Salvador Sierra, Tina M. O’Grady, Mario de la Fuente Revenga, Florent Laval, Vladimir V. Botchkarev, Christoph Gorgulla, Paul W. Coote, Jérémy Blavier, Ezekiel A. Geffken, Jimit Lakhani, Kijun Song, Zoe C. Yeoh, Bin Hu, Anthony C. Varca, Jonathan Bruyr, Samira Ibrahim, Tasneem Jivanjee, Joshua D. Bromley, Sarah K. Nyquist, Aaron Richardson, Hong Yue, Yang Wang, Natalia Calonghi, Alessandra Stefan, Kerstin Spirohn, Didier Vertommen, Maria F. Baietti, Irma Lemmens, Hyuk-Soo Seo, Mikhail G. Dozmorov, Luc Willems, Jan Tavernier, Kalyan Das, Eleonora Leucci, Alejandro Hochkoeppler, Zhen-Yu Jim Sun, Michael A. Calderwood, Tong Hao, Alex K. Shalek, David E. Hill, Andras Boeszoermenyi, Haribabu Arthanari, Sara J. Buhrlage, Sirano Dhe-Paganon, Javier González-Maeso, Franck Dequiedt, Jean-Claude Twizere, and Marc Vidal
- Abstract
Enzymatic pockets such as those of histone deacetylases (HDACs) are among the most favored targets for drug development. However, enzymatic inhibitors often exhibit low selectivity and high toxicity due to targeting multiple enzyme paralogs, which are often involved in distinct multisubunit complexes. Here, we report the discovery and characterization of a non-enzymatic small molecule inhibitor of HDAC transcriptional repression functions with comparable anti-tumor activity to the enzymatic HDAC inhibitor Vorinostat, and anti-psychedelic activity of anHDAC2knockoutin vivo. We highlight that these phenotypes are achieved while modulating the expression of 20- and 80-fold fewer genes than enzymatic and genetic inhibition in the respective models. Thus, by achieving the same biological outcomes as established therapeutics while impacting a dramatically smaller number of genes, inhibitors of protein-protein interactions can offer important advantages in improving the selectivity of epigenetic modulators.GRAPHICAL ABSTRACT
- Published
- 2022
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