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 an HDAC2 knockout in 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.
Competing Interest Statement
An unpublished patent application where J.O., J.C.T., M.V., S.G.C. and S.J.B. are listed as co-inventors has been filed related to this article. M.d.l.F.R. has a consulting agreement with Noetic Fund. C.G. is a co-founder of Quantum Therapeutics Inc. and Virtual Discovery Inc. A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Hovione, Third Rock Ventures, Ochre Bio, FL82, Empress Therapeutics, Relation Therapeutics, Senda Biosciences, IntrECate biotherapeutics, and Dahlia Biosciences unrelated to this work. A.K.S. has received research support from Merck, Novartis, Leo Pharma, Janssen, the Bill and Melinda Gates Foundation, the Moore Foundation, the NIH, Wellcome Leap, the Pew-Stewart Trust, Foundation MIT, the Chan Zuckerberg Initiative, Novo Nordisk and the FDA unrelated to this work. All other authors declare that they have no competing interests.
Footnotes
Manuscript updated to reflect the latest changes in title, abstract, introduction, and discussion, and to make the graphical abstract directly visible on the bioRxiv webpage of the article.
