Discovery of Small-Molecule Antagonists of the H3K9me3 Binding to UHRF1 Tandem Tudor Domain. (October 2018)

• Record Type: Journal Article
• Authors: Senisterra, Guillermo; Zhu, Hugh Y.; Luo, Xiao; Zhang, Hailong; Xun, Guoliang; Lu, Chunliang; Xiao, Wen; Hajian, Taraneh; Loppnau, Peter; Chau, Irene; Li, Fengling; Allali-Hassani, Abdellah; Atadja, Peter; Oyang, Counde; Li, En; Brown, Peter J.; Arrowsmith, Cheryl H.; Zhao, Kehao; Yu, Zhengtian; Vedadi, Masoud
• Is Part Of: SLAS discovery. Volume 23:Number 9(2018)
• Page Start: 930
• Page End: 940
• Publication Date: 2018-10
• Subjects: UHRF1 -- DNMT1 -- cancer and cancer drugs -- tandem tudor domain; Drugs -- Analysis -- Periodicals; Drugs -- Testing -- Periodicals; Biomolecules -- Analysis -- Periodicals; Biomolecules -- Analysis; Drugs -- Analysis; Drugs -- Testing; Drug Evaluation, Preclinical; Molecular Biology -- methods; Periodicals; Periodicals; 615.1
• DOI: 10.1177/2472555218766278
• Languages: English
• ISSNs: 2472-5552

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 Kd value 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 (Kd of 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.