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. 2025 May 5;16(6):1080-1088.
doi: 10.1021/acsmedchemlett.5c00116. eCollection 2025 Jun 12.

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

Wenwei Lin  1 , P Jake Slavish  1 , Aaron H Phillips  1 , Marlon Trotter  1 , Guangwei Yang  1 , Sergio C Chai  1 , Kelly Churion  1 , Jason Ochoada  1 , Sourav Das  1 , Anang A Shelat  1 , Charles G Mullighan  1 , Richard W Kriwacki  1 , Zoran Rankovic  1 , Taosheng Chen  1
Affiliations

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

Wenwei Lin et al. ACS Med Chem Lett. .

Abstract

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.

Keywords: H3K4Me3; HTS; NUP98-KDM5A PHD3; TR-FRET.

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