Which Histone (De)Methyltransferase modulators to choose?

Histone Methyltransferases (ex. EZH1 and EZH2, and G9a) and their counter-parts (Histone demethylases like JARID1, the KDM4, and the JMJD family) have become promising targets for inhibitor screenings, especially in Cancer drug discovery. (1, 2) Accessing a wide variety of pure and well-characterized bioactive small molecules is of importance when characterizing these enzymes.

Here, we’ve compiled a list of 19 bioactive compounds currently seen in the literature when studying Histone Methyltransferases and Demethylases in Drug Discovery.

Histone Methyltransferase-specific modulators

• 3-Deazaneplanocin – Cell-permeable inhibitor of the histone methyltransferase EZH2.
• 3-Deazaneplanocin A (DZNep) hydrochloride  – 3-Deazaneplanocin A (DZNep) is an S-Adenosylhomocysteine Hydrolase inhibitor and histone methyltransferase EZH2 inhibitor.
• BIX-01294  – Selective inhibitor of G9a.
• Chaetocin – Inhibitor HMTs including SUV39H1 and Lys9-specific HMTs such as G9a. Also has some inhibitory effects on SET7, EZH2, and SET7/9.
• Ellagic acid – HMT Inhibitor, it can block methylation of arginine 17 of histone 3 (H3R17) by coactivator-associated arginine methyltransferase 1 (CARM1), or PRMT4, without significantly altering histone acetylase or DNA methyltransferase activity.
• EPZ-6438 – Potent and bio-available inhibitor of EZH2.
• EPZ005687 – Potent and selective inhibitor of EZH2.
• EPZ5676 – Inhibitor of protein methyltransferase DOT1L.
• SGC 0946 – Potent small-molecule inhibitor specific for protein methyltransferase DOT1L.
• UNC0224 – Potent and selective inhibitor of G9a.
• UNC0321 (trifluoroacetate salt) – Selective HMTase inhibitor for G9a and GLP, more than 40,000-fold more selective for G9a and GLP vs. SET7/9, SET8, PRMT3, or JMJD2E.
• UNC0638 – Potent inhibitor of histone methyltransferases (HMT) including G9a and GLP, and SET7/9, SET8, PRMT3 and SUV39H2.
• UNC1999 – Selective inhibitor of EZH2 and EZH1.

Histone Demethylase-specific modulators

• Daminozide – Selective inhibitor of the KDM2/7 JmjC subfamily of histone demethylases.
• GSK-J1 – Potent and selective inhibitor of jumonji H3K27 histone demethylases JMJD3 and UTX.

  

• GSK J4 HCl – Cell permeable prodrug of GSK J1, which is the first selective inhibitor of the H3K27 histone demethylase JMJD3 and UTX.
• IOX 1 –  Inhibitor of the JMJD family of 2-oxoglutarate-dependent histone demethylases.
• OG-L002 – Specific inhibitor of LSD1.
• Tranylcypromine -Irreversible inhibitor of LSD1 histone demethylase and monoamine oxidases.

Interested in any of these Demethylase and Methyltransferase inhibitors, or any others? Get in touch with me with by leaving your question below!

References:

1. Cloos P.A. et al. “The putative oncogene GASC1 demethylates tri- and dimethylated lysine 9 on histone H3″ (2006) Nature 442, pp. 307-311.
2. Chan F. et al. “Methylation of Lysine 9 of Histone H3: Role of Heterochromatin Modulation and Tumorigenesis, in T. ollefsbol, Handbook of Epigenetics: The New Molecular and Medical Genetics” (2010) Boston: Academic Press. pp. 149–157.