title: 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.
authors.affiliation: MRC Laboratory of Molecular Biology , Francis Crick Avenue, Cambridge CB2 0QH, United Kingdom.
authors.forename: Thomas C R
authors.initials: TC
authors.lastname: Miller
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Rutherford
authors.forename: Kristian
authors.initials: K
authors.lastname: Birchall
authors.forename: Jasveen
authors.initials: J
authors.lastname: Chugh
authors.forename: Marc
authors.initials: M
authors.lastname: Fiedler
authors.forename: Mariann
authors.initials: M
authors.lastname: Bienz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry*; D001562:Benzimidazoles / Q000737:chemistry*; D052160:Benzothiazoles / Q000737:chemistry*; D001665:Binding Sites; D001667:Binding, Competitive; D002843:Chromatin / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006657:Histones / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; C111180:BCL9 protein, human; D001562:Benzimidazoles; D052160:Benzothiazoles; D002843:Chromatin; D006657:Histones; D008024:Ligands; D009363:Neoplasm Proteins; C453402:PYGO1 protein, human; D011994:Recombinant Proteins; D014157:Transcription Factors