HTS Identifies NUP98-KDM5A-PHD3 Domain Ligands with Novel Scaffolds
NUP98-KDM5A oncogenic fusion protein contains the N-terminal FG-repeat domain of NUP98 and the C-terminal PHD3 finger of KDM5A. Pediatric acute myeloid leukemia patients with NUP98-KDM5A have poor prognosis and high incidence of relapse and urgently need novel therapeutics. We developed a TR-FRET assay to detect the interaction between the PHD3 domain and a H3K4-(Me3) peptide and screened a library comprising over 600,000 compounds, leading to the identification of KDM5A-PHD3 domain ligands with novel scaffolds, such as CBL-0137, UNBS5162, BIX-01294, and 3-phenyl-toxoflavin, which were subsequently confirmed via SPR and/or NMR assays. These ligands hold significant promise for therapeutic interventions in pediatric acute myeloid leukemia driven by NUP98-KDM5A, pending further development.
Authors
- Aaron H. Phillips (ORCID: https://orcid.org/0000-0003-0245-5124)
- Taosheng Chen (ORCID: https://orcid.org/0000-0001-6420-3809)
- Richard W. Kriwacki (ORCID: https://orcid.org/0000-0002-9798-6018)
- Zoran Ranković (ORCID: https://orcid.org/0000-0001-6866-4290)
- Kelly Churion (ORCID: https://orcid.org/0000-0002-4346-7562)
- Charles Grenfell Mullighan (ORCID: https://orcid.org/0000-0002-1871-1850)
- Sergio C. Chai (ORCID: https://orcid.org/0000-0002-8257-8599)
- Jason Ochoada (ORCID: https://orcid.org/0000-0003-0728-8820)
- Wenwei Lin (ORCID: https://orcid.org/0000-0001-8754-6150)
- Anang A. Shelat (ORCID: https://orcid.org/0000-0002-6266-2910)
- Matthew Trotter (ORCID: https://orcid.org/0000-0003-3702-915X)
- P.J. Slavish (ORCID: https://orcid.org/0000-0002-0043-4322)
- Sourav Das (ORCID: https://orcid.org/0000-0002-2576-0482)
- Guangwei Yang
Institutions
- St. Jude Children's Research Hospital (US)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2025-05-05
- DOI
- https://doi.org/10.1021/acsmedchemlett.5c00116
- Primary Topic
- Metal-Catalyzed Oxygenation Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Cancer Institute