A Chemical Probe for the ATAD2 Bromodomain. Issue 38 (17th August 2016)

• Record Type: Journal Article
• Authors: Bamborough, Paul; Chung, Chun‐wa; Demont, Emmanuel H.; Furze, Rebecca C.; Bannister, Andrew J.; Che, Ka Hing; Diallo, Hawa; Douault, Clement; Grandi, Paola; Kouzarides, Tony; Michon, Anne‐Marie; Mitchell, Darren J.; Prinjha, Rab K.; Rau, Christina; Robson, Samuel; Sheppard, Robert J.; Upton, Richard; Watson, Robert J.
• Is Part Of: Angewandte Chemie international edition. Volume 55:Issue 38(2016)
• Page Start: 11382
• Page End: 11386
• Publication Date: 2016-08-17
• Subjects: bioisosteres -- conformation analysis -- epigenetics -- fluorine -- medicinal chemistry; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201603928
• Languages: English
• ISSNs: 1433-7851

Abstract

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. Abstract : ANCCA away : ATAD2 or ANCCA is a cancer‐associated bromodomain‐containing protein. Starting from a potent lead, permeability and selectivity over BET bromodomains were improved by 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. GSK8814 is the first low‐nanomolar, selective and cell‐permeable chemical probe for ATAD2.