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.
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.
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