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Related Experiment Video

Updated: Sep 18, 2025

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HTS Identifies NUP98-KDM5A-PHD3 Domain Ligands with Novel Scaffolds.

Wenwei Lin1, P Jake Slavish1, Aaron H Phillips1

  • 1†Department of Chemical Biology and Therapeutics, ‡Department of Structural Biology, and §Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, United States.

ACS Medicinal Chemistry Letters
|June 25, 2025
PubMed
Summary

Researchers identified novel drug compounds targeting the NUP98-KDM5A fusion protein, offering hope for treating pediatric acute myeloid leukemia (AML) with poor prognosis.

Keywords:
H3K4Me3HTSNUP98-KDM5A PHD3TR-FRET

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Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • NUP98-KDM5A is an oncogenic fusion protein implicated in pediatric acute myeloid leukemia (AML).
  • Patients with NUP98-KDM5A AML exhibit poor prognosis and frequent relapses, necessitating new therapeutic strategies.

Purpose of the Study:

  • To identify novel small molecules that inhibit the interaction of the KDM5A-PHD3 domain with H3K4-(Me3) peptides.
  • To discover potential therapeutic agents for NUP98-KDM5A-driven pediatric AML.

Main Methods:

  • Development of a TR-FRET assay to screen for KDM5A-PHD3 domain ligands.
  • Screening of a compound library exceeding 600,000 molecules.
  • Validation of identified ligands using Surface Plasmon Resonance (SPR) and Nuclear Magnetic Resonance (NMR) assays.

Main Results:

  • Identification of several novel KDM5A-PHD3 domain ligands with unique scaffolds.
  • Confirmed ligands include CBL-0137, UNBS5162, BIX-01294, and 3-phenyl-toxoflavin.
  • These compounds demonstrate potential for targeting the NUP98-KDM5A fusion protein.

Conclusions:

  • The identified ligands represent promising candidates for the development of targeted therapies against NUP98-KDM5A pediatric AML.
  • Further preclinical development of these novel compounds is warranted.