Back to Search
Start Over
Discovery of Small-Molecule Antagonists of the H3K9me3 Binding to UHRF1 Tandem Tudor Domain
- Source :
- Journal of Biomolecular Screening; October 2018, Vol. 23 Issue: 9 p930-940, 11p
- Publication Year :
- 2018
-
Abstract
- Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is a multidomain protein that plays a critical role in maintaining DNA methylation patterns through concurrent recognition of hemimethylated DNA and histone marks by various domains, and recruitment of DNA methyltransferase 1 (DNMT1). UHRF1 is overexpressed in various cancers, including breast cancer. The tandem tudor domain (TTD) of UHRF1 specifically and tightly binds to histone H3 di- or trimethylated at lysine 9 (H3K9me2 or H3K9me3, respectively), and this binding is essential for UHRF1 function. We developed an H3K9me3 peptide displacement assay, which was used to screen a library of 44,000 compounds for small molecules that disrupt the UHRF1-H3K9me3 interaction. This screen resulted in the identification of NV01, which bound to UHRF1-TTD with a Kdvalue of 5 μM. The structure of UHRF1-TTD in complex with NV01 confirmed binding to the H3K9me3-binding pocket. Limited structure-based optimization of NV01 led to the discovery of NV03 (Kdof 2.4 μM). These well-characterized small-molecule antagonists of the UHRF1-H3K9me2/3 interaction could be valuable starting chemical matter for developing more potent and cell-active probes toward further characterizing UHRF1 function, with possible applications as anticancer therapeutics.
Details
- Language :
- English
- ISSN :
- 10870571 and 1552454X
- Volume :
- 23
- Issue :
- 9
- Database :
- Supplemental Index
- Journal :
- Journal of Biomolecular Screening
- Publication Type :
- Periodical
- Accession number :
- ejs46568991
- Full Text :
- https://doi.org/10.1177/2472555218766278