A Chemical Probe for the ATAD2 Bromodomain.

A Chemical Probe for the ATAD2 Bromodomain.

Angewandte Chemie (International ed. in English) (2016-08-18)

Paul Bamborough, Chun-Wa Chung, Emmanuel H Demont, Rebecca C Furze, Andrew J Bannister, Ka Hing Che, Hawa Diallo, Clement Douault, Paola Grandi, Tony Kouzarides, Anne-Marie Michon, Darren J Mitchell, Rab K Prinjha, Christina Rau, Samuel Robson, Robert J Sheppard, Richard Upton, Robert J Watson

PMID27530368

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.