Fragment-Based NMR Screening of the BPTF PHD Finger Methyl Lysine Reader Leads to the First Small Molecule Inhibitors

14 August 2023, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


Methyl lysine readers, specifically PHD fingers, are emerging epigenetic targets in human diseases. For example, several PHD finger fusions are implicated in clinical cases of acute myeloid leukemia, highlighting the potential for PHD inhibitors in disease regulation. However, limited chemical matter exists targeting PHD fingers. Here we report the first fragment-based screen against the BPTF PHD to identify several of the first reported BPTF PHD-targeting small molecule ligands. We used ligand-observed NMR to first screen a fragment library, followed by biophysical validation to prioritize two scaffolds, pyr-rolidine- and pyridazine-containing fragments. Structural predictions show these respective scaffolds may engage two distinct subpockets on the protein. The demonstrated ligandability of the BPTF PHD supports the future development of methyl lysine reader chemical probes to study their oncogenic functions.


fragment-based drug discovery
methyl lysine reader
NMR screen
nucleosome remodeler

Supplementary materials

Supplementary material
Small molecule characterization and biophysical characterization data


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