N-Oxalylglycine

The jumonji domain-containing protein 2 (JMJD2) subfamily of histone demethylases have been shown to catalyze demethylation of the methylated forms of histone 3 lysine 9 (H3K9) and H3K36 in vitro and in cells.¹ Because histone demethylases are implicated in certain diseases, including cancer, selective inhibitors are candidate anticancer agents as well as potential tools for elucidating the biological functions of JMJDs.² N-Oxalylglycine, the amide analog of α-ketoglutarate, is a cell permeable inhibitor of α-ketoglutarate-dependent enzymes, including JMJD2A, JMJD2C, and JMJD2E (IC₅₀s = 250, 500, and 24 μM, respectively).^3,4,5,6 It can also inhibit the prolyl hydroxylase domain-containing proteins PHD1 and PHD2 with IC₅₀ values of 2.1 and 5.6 μM, respectively.^4,5,7

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1. Krishnan, S., Horowitz, S., and Trievel, R.C. Structure and function of histone H3 lysine 9 methyltransferases and demethylases. Chembiochem 12(2), 254-263 (2011).

2. Tian, X., and Fang, J. Current perspectives on histone demethylases. Acta Biochim. Biophys. Sin. (Shanghai) 39(2), 81-88 (2007).

3. Hamada, S., Kim, T.D., Suzuki, T., et al. Synthesis and activity of N-oxalylglycine and its derivatives as Jumonji C-domain-containing histone lysine demethylase inhibitors. Bioorg. Med. Chem. Lett. 19(10), 2852-2855 (2009).

4. Hamada, S., Suzuki, T., Mino, K., et al. Design, synthesis, enzyme-inhibitory activity, and effect on human cancer cells of a novel series of Jumonji domain-containing protein 2 histone demethylase inhibitors. J. Med. Chem. 53(15), 5629-5638 (2010).

5. Rose, N.R., Ng, S.S., Mecinovic, J., et al. Inhibitor scaffolds for 2-oxoglutarate-dependent histone lysine demethylases. J. Med. Chem. 51(22), 7053-7056 (2008).

6. Rose, N.R., Woon, E.C.Y., Kingham, G.L., et al. Selective inhibitors of the JMJD2 histone demethylases: Combined nondenaturing mass spectrometric screening and crystallographic approaches. J. Med. Chem. 53(4), 1810-1818 (2010).

Aggarwal, G., Zarrow, J.E., Mashhadi, Z., et al. Symmetrically substituted dichlorophenes inhibit N-acyl-phosphatidylethanolamine phospholipase D. The Journal of Biological Chemisty 295(21), 7289-7300 (2020).