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

Caroline R. Buchholz, Molly S. Sneddon, Joseph E. McPherson, Sourav Das, Clifford T. Gee, Michael J. Grillo, Sergio C. Chai, Richard E. Lee, Taosheng Chen, Daniel A. Harki, Anang A. Shelat, William C.K. Pomerantz

Research output: Contribution to journalArticlepeer-review

Abstract

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 targeting PHD fingers exists. 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, pyrrolidine- and pyridazine-containing fragments. Structural predictions show that 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.

Original languageEnglish (US)
Pages (from-to)1441-1447
Number of pages7
JournalACS Medicinal Chemistry Letters
Volume14
Issue number10
DOIs
StatePublished - Oct 12 2023

Bibliographical note

Publisher Copyright:
© 2023 American Chemical Society.

Keywords

  • BPTF
  • Epigenetics
  • Fragment-based screening
  • Methyl lysine reader
  • PHD finger

PubMed: MeSH publication types

  • Journal Article

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