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5-substituted pyridine-2,4-dicarboxylate derivatives have potential for selective inhibition of human jumonji-c domain-containing protein 5

DOI: 10.1021/acs.jmedchem.3c01114 DOI Help

Authors: Lennart Brewitz (University of Oxford) , Yu Nakashima (University of Oxford) , Sonia K. Piasecka (University of Birmingham) , Eidarus Salah (University of Oxford) , Sally C. Fletcher (University of Birmingham) , Anthony Tumber (University of Oxford) , Thomas P. Corner (University of Oxford) , Tristan J. Kennedy (niversity of Birmingham) , Giorgia Fiorini (University of Oxford) , Armin Thalhammer (University of Oxford) , Kirsten E. Christensen (University of Oxford) , Mathew L. Coleman (University of Birmingham) , Christopher J. Schofield (University of Oxford)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 8

State: Published (Approved)
Published: August 2023
Diamond Proposal Number(s): 23459

Open Access Open Access

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 Nε-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.

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I03-Macromolecular Crystallography , I24-Microfocus Macromolecular Crystallography

Other Facilities: ID30A-1 at ERSF

Added On: 04/08/2023 08:27

Documents:
acs.jmedchem.3c01114.pdf

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)