Download Mendeley5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5.
Brewitz, L., Nakashima, Y., Piasecka, S.K., Salah, E., Fletcher, S.C., Tumber, A., Corner, T.P., Kennedy, T.J., Fiorini, G., Thalhammer, A., Christensen, K.E., Coleman, M.L., Schofield, C.J.(2023) J Med Chem 66: 10849-10865
- PubMed: 37527664
- DOI: https://doi.org/10.1021/acs.jmedchem.3c01114
- Primary Citation of Related Structures:
7DYT, 7DYU, 7DYV, 7DYW, 7DYX - PubMed Abstract:
Jumonji-C domain-containing protein 5 (JMJD5) is a 2-oxoglutarate (2OG)-dependent oxygenase that plays important roles in development, circadian rhythm, and cancer through unclear mechanisms. JMJD5 has been reported to have activity as a histone protease, as an N ε -methyl lysine demethylase, and as an arginine residue hydroxylase. Small-molecule JMJD5-selective inhibitors will be useful for investigating its (patho)physiological roles. Following the observation that the broad-spectrum 2OG oxygenase inhibitor pyridine-2,4-dicarboxylic acid (2,4-PDCA) is a 2OG-competing JMJD5 inhibitor, we report that 5-aminoalkyl-substituted 2,4-PDCA derivatives are potent JMJD5 inhibitors manifesting selectivity for JMJD5 over other human 2OG oxygenases. Crystallographic analyses with five inhibitors imply induced fit binding and reveal that the 2,4-PDCA C5 substituent orients into the JMJD5 substrate-binding pocket. Cellular studies indicate that the lead compounds display similar phenotypes as reported for clinically observed JMJD5 variants, which have a reduced catalytic activity compared to wild-type JMJD5.
- Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, OX1 3TA Oxford, U.K.
Organizational Affiliation:
