Discovery of Small Molecules Targeting the Tandem Tudor Domain of the Epigenetic Factor UHRF1 Using Fragment-Based Ligand Discovery

Authors

Lyra Chang
James Campbell
Idris O Raji
Shiva K R Guduru
Prasanna Kandel
Michelle Nguyen
Steven Liu
Kevin Tran
Navneet K Venugopal
Bethany C Taylor
Matthew V Holt
Nicolas L Young
Errol L G Samuel
Prashi Jain
Conrad Santini
Banumathi Sankaran
Kevin R MacKenzie
Damian W Young

Publication Date

1-13-2021

Journal

Scientific Reports

DOI

10.1038/s41598-020-80588-4

PMID

33441849

PMCID

PMC7806715

PubMedCentral® Posted Date

1-13-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Binding Sites, CCAAT-Enhancer-Binding Proteins, Crystallography, X-Ray, Drug Discovery, Histone Code, Histones, Ligands, Magnetic Resonance Spectroscopy, Molecular Structure, Peptide Fragments, Protein Binding, Pyridines, Small Molecule Libraries, Structure-Activity Relationship, Tudor Domain, Ubiquitin-Protein Ligases, Chemical tools, Cancer, Drug screening

Abstract

Despite the established roles of the epigenetic factor UHRF1 in oncogenesis, no UHRF1-targeting therapeutics have been reported to date. In this study, we use fragment-based ligand discovery to identify novel scaffolds for targeting the isolated UHRF1 tandem Tudor domain (TTD), which recognizes the heterochromatin-associated histone mark H3K9me3 and supports intramolecular contacts with other regions of UHRF1. Using both binding-based and function-based screens of a ~ 2300-fragment library in parallel, we identified 2,4-lutidine as a hit for follow-up NMR and X-ray crystallography studies. Unlike previous reported ligands, 2,4-lutidine binds to two binding pockets that are in close proximity on TTD and so has the potential to be evolved into more potent inhibitors using a fragment-linking strategy. Our study provides a useful starting point for developing potent chemical probes against UHRF1.