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A Chemical Probe for the ATAD2 Bromodomain.

ABSTRACT: ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.

SUBMITTER: Bamborough P

PROVIDER: S-EPMC7314595 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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A Chemical Probe for the ATAD2 Bromodomain.

Bamborough Paul P Chung Chun-Wa CW Demont Emmanuel H EH Furze Rebecca C RC Bannister Andrew J AJ Che Ka Hing KH Diallo Hawa H Douault Clement C Grandi Paola P Kouzarides Tony T Michon Anne-Marie AM Mitchell Darren J DJ Prinjha Rab K RK Rau Christina C Robson Samuel S Sheppard Robert J RJ Upton Richard R Watson Robert J RJ

Angewandte Chemie (International ed. in English) 20160817 38

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2. ...[more]

PMID: 27530368

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