The optimization of potent ATAD2 and CECR2 bromodomain inhibitors with an atypical binding mode
| Autor: | Chun-wa Chung, Rab K. Prinjha, Simon C. C. Lucas, Nicholas C. O. Tomkinson, Alexander N Phillipou, Stephen John Atkinson, Darren Jason Mitchell, Paul Bamborough, Robert J. Sheppard, Emmanuel Hubert Demont, Robert J. Watson, Laurie J. Gordon, Heather A. Barnett |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Stereochemistry
Lysine 01 natural sciences Protein Structure Secondary 03 medical and health sciences Protein structure Protein Domains Drug Discovery Humans QD Asparagine Tyrosine 030304 developmental biology Sulfonamides 0303 health sciences biology Chemistry HEK 293 cells 0104 chemical sciences Bromodomain DNA-Binding Proteins 010404 medicinal & biomolecular chemistry HEK293 Cells Histone Acetylation biology.protein ATPases Associated with Diverse Cellular Activities Molecular Medicine Protein Binding Transcription Factors |
| ISSN: | 0022-2623 |
| Popis: | Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties. |
| Databáze: | OpenAIRE |
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