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Competitive binding of a benzimidazole to the histone-binding pocket of the Pygo PHD finger.

Abstract：

:The Pygo-BCL9 complex is a chromatin reader, facilitating β-catenin-mediated oncogenesis, and is thus emerging as a potential therapeutic target for cancer. Its function relies on two ligand-binding surfaces of Pygo's PHD finger that anchor the histone H3 tail methylated at lysine 4 (H3K4me) with assistance from the BCL9 HD1 domain. Here, we report the first use of fragment-based screening by NMR to identify small molecules that block protein-protein interactions by a PHD finger. This led to the discovery of a set of benzothiazoles that bind to a cleft emanating from the PHD-HD1 interface, as defined by X-ray crystallography. Furthermore, we discovered a benzimidazole that docks into the H3K4me specificity pocket and displaces the native H3K4me peptide from the PHD finger. Our study demonstrates the ligandability of the Pygo-BCL9 complex and uncovers a privileged scaffold as a template for future development of lead inhibitors of oncogenesis.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Miller TC,Rutherford TJ,Birchall K,Chugh J,Fiedler M,Bienz M

doi

10.1021/cb500585s

subject

Has Abstract

pub_date

2014-12-19 00:00:00

pages

2864-74

issue

12

eissn

1554-8929

issn

1554-8937

journal_volume

9

pub_type

杂志文章

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