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Profiling Inhibitor Scaffolds for the Cancer Target Jumonji-C Domain-Containing Protein 6

Thomas P Corner1, Eidarus Salah1, Anthony Tumber1

  • 1Chemistry Research Laboratory, Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, UK.

Chemmedchem
|October 31, 2025
PubMed

Insights

Researchers developed a new assay to find JMJD6 inhibitors for prostate cancer treatment. Some existing drugs for other conditions effectively inhibit JMJD6, suggesting a new therapeutic avenue.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Jumonji-C domain-containing protein 6 (JMJD6) is a human enzyme involved in post-translational modifications.
  • Dysregulated JMJD6 activity correlates with androgen receptor splice variant 7 (AR-V7) upregulation, a mechanism driving resistance to antiandrogen therapies in prostate cancer.
  • JMJD6 is recognized as a potential therapeutic target for prostate cancer due to its role in treatment resistance.

Purpose of the Study:

  • To establish and validate a robust assay for screening small-molecule inhibitors of isolated JMJD6.
  • To identify novel chemical scaffolds with potential for developing selective JMJD6 inhibitors.
  • To investigate the inhibitory activity of known JMJD6 inhibitors and clinical drugs against isolated JMJD6.

Main Methods:

  • Development of a solid-phase extraction coupled to mass spectrometry (SPE-MS) assay for monitoring JMJD6 catalytic activity.
  • Screening of previously reported JMJD6 inhibitors (WL12, SKLB325, Compound 7p) using the developed SPE-MS assay.
  • Evaluation of the in vitro inhibitory effects of clinically used hypoxia-inducible factor-α prolyl hydroxylase domain-containing protein (PHD) inhibitors (Enarodustat, Desidustat) on isolated JMJD6.

Main Results:

  • The developed SPE-MS assay provides a reliable method for assessing small-molecule inhibition of JMJD6.
  • Previously reported JMJD6 inhibitors demonstrated limited efficacy in vitro.
  • Certain clinical PHD inhibitors, specifically Enarodustat and Desidustat, exhibited potent inhibition of isolated JMJD6.
  • This suggests that JMJD6 inhibition may be an off-target effect of these clinically used PHD inhibitors.

Conclusions:

  • The study presents an effective assay for identifying and characterizing JMJD6 inhibitors.
  • Attractive chemical scaffolds for developing selective and cell-permeable JMJD6 inhibitors were identified.
  • The findings indicate that JMJD6 inhibition could be an unintended consequence of using certain PHD inhibitors in clinical settings, warranting further investigation.
Keywords:
2‐oxoglutarate/α‐ketoglutarate‐dependent oxygenaseDesidustatEnarodustatJmjC hydroxylase inhibitionJumonji‐C domain‐containing protein 6bromodomain‐containing protein 4high‐throughput inhibition assaysinhibitor discoverymetastatic castration‐resistant prostate cancer

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