Epigenetics

Epigenetics is a growing and promising area of drug discovery research. To date, efforts in this direction have led to over 100 clinical candidates and seven FDA-approved drugs [1-2]. The main idea behind epigenetics is to alter or completely silence gene expression of disease-relevant targets. The general biology can be described as a dynamic balance between (1) writer enzymes (introduce structural modifications of the nucleic acids), (2) reader enzymes (recognize modifications introduces), and (3) eraser enzymes (remove modifications) [3]. All parts of this mechanism can in principle be viewed as potential drug targets. To complicate things further, there are also a lot of types of epigenetic modifications already known and probably more yet to be discovered. Following the authors' perspective [3], it is convenient to highlight the two arguably the most important:
•    Methylation (DNA and protein)
•    Acetylation (mostly protein targets)

Work in this area over the past several decades has shown that small molecules are ideally suited to their role in modifying both these types. Moreover, all types of enzymes regulating epigenetic functions are considered druggable. Described mechanisms of action range from "classic" disruption of catalytic turnover to inhibition of protein-protein interactions (as observed with BET inhibitors).

ChemDiv is pleased to offer its own custom libraries focused on the following epigenetic targets:
•    Histone Deacetylases (HDAC) Targeted Library (https://www.chemdiv.com/catalog/focused-and-targeted-libraries/histone-deacetylases-hdac-targeted-library-selection/)
•    Bromodomain Modulators Library (https://www.chemdiv.com/catalog/focused-and-targeted-libraries/bromodomain-modulators-library/)
•    Protein Arginine Methyltransferases Library (https://www.chemdiv.com/catalog/focused-and-targeted-libraries/prmt-library/)

1. Ganesan A, Arimondo PB, Rots MG, Jeronimo C, Berdasco M. The timeline of epigenetic drug discovery: from reality to dreams. Clin Epigenetics. 2019 Dec 2;11(1):174. doi: 10.1186/s13148-019-0776-0. PMID: 31791394; PMCID: PMC6888921.
2. Bates SE. Epigenetic Therapies for Cancer. N Engl J Med. 2020 Aug 13;383(7):650-663. doi: 10.1056/NEJMra1805035. PMID: 32786190.
3. Vaidergorn MM, da Silva Emery F, Ganesan A. From Hit Seeking to Magic Bullets: The Successful Union of Epigenetic and Fragment Based Drug Discovery (EPIDD + FBDD). J Med Chem. 2021 Oct 14;64(19):13980-14010. doi: 10.1021/acs.jmedchem.1c00787. Epub 2021 Sep 30. PMID: 34591474.