Cargando…
5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5
[Image: see text] 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 d...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Chemical Society
2023
|
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10424186/ https://www.ncbi.nlm.nih.gov/pubmed/37527664 http://dx.doi.org/10.1021/acs.jmedchem.3c01114 |
_version_ | 1785089620475641856 |
---|---|
author | Brewitz, Lennart Nakashima, Yu Piasecka, Sonia K. Salah, Eidarus Fletcher, Sally C. Tumber, Anthony Corner, Thomas P. Kennedy, Tristan J. Fiorini, Giorgia Thalhammer, Armin Christensen, Kirsten E. Coleman, Mathew L. Schofield, Christopher J. |
author_facet | Brewitz, Lennart Nakashima, Yu Piasecka, Sonia K. Salah, Eidarus Fletcher, Sally C. Tumber, Anthony Corner, Thomas P. Kennedy, Tristan J. Fiorini, Giorgia Thalhammer, Armin Christensen, Kirsten E. Coleman, Mathew L. Schofield, Christopher J. |
author_sort | Brewitz, Lennart |
collection | PubMed |
description | [Image: see text] 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. |
format | Online Article Text |
id | pubmed-10424186 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Chemical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-104241862023-08-15 5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5 Brewitz, Lennart Nakashima, Yu Piasecka, Sonia K. Salah, Eidarus Fletcher, Sally C. Tumber, Anthony Corner, Thomas P. Kennedy, Tristan J. Fiorini, Giorgia Thalhammer, Armin Christensen, Kirsten E. Coleman, Mathew L. Schofield, Christopher J. J Med Chem [Image: see text] 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. American Chemical Society 2023-08-01 /pmc/articles/PMC10424186/ /pubmed/37527664 http://dx.doi.org/10.1021/acs.jmedchem.3c01114 Text en © 2023 The Authors. Published by American Chemical Society https://creativecommons.org/licenses/by/4.0/Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Brewitz, Lennart Nakashima, Yu Piasecka, Sonia K. Salah, Eidarus Fletcher, Sally C. Tumber, Anthony Corner, Thomas P. Kennedy, Tristan J. Fiorini, Giorgia Thalhammer, Armin Christensen, Kirsten E. Coleman, Mathew L. Schofield, Christopher J. 5-Substituted Pyridine-2,4-dicarboxylate Derivatives Have Potential for Selective Inhibition of Human Jumonji-C Domain-Containing Protein 5 |
title | 5-Substituted
Pyridine-2,4-dicarboxylate Derivatives
Have Potential for Selective Inhibition of Human Jumonji-C
Domain-Containing Protein 5 |
title_full | 5-Substituted
Pyridine-2,4-dicarboxylate Derivatives
Have Potential for Selective Inhibition of Human Jumonji-C
Domain-Containing Protein 5 |
title_fullStr | 5-Substituted
Pyridine-2,4-dicarboxylate Derivatives
Have Potential for Selective Inhibition of Human Jumonji-C
Domain-Containing Protein 5 |
title_full_unstemmed | 5-Substituted
Pyridine-2,4-dicarboxylate Derivatives
Have Potential for Selective Inhibition of Human Jumonji-C
Domain-Containing Protein 5 |
title_short | 5-Substituted
Pyridine-2,4-dicarboxylate Derivatives
Have Potential for Selective Inhibition of Human Jumonji-C
Domain-Containing Protein 5 |
title_sort | 5-substituted
pyridine-2,4-dicarboxylate derivatives
have potential for selective inhibition of human jumonji-c
domain-containing protein 5 |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10424186/ https://www.ncbi.nlm.nih.gov/pubmed/37527664 http://dx.doi.org/10.1021/acs.jmedchem.3c01114 |
work_keys_str_mv | AT brewitzlennart 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT nakashimayu 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT piaseckasoniak 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT salaheidarus 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT fletchersallyc 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT tumberanthony 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT cornerthomasp 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT kennedytristanj 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT fiorinigiorgia 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT thalhammerarmin 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT christensenkirstene 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT colemanmathewl 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 AT schofieldchristopherj 5substitutedpyridine24dicarboxylatederivativeshavepotentialforselectiveinhibitionofhumanjumonjicdomaincontainingprotein5 |