A Chemical Probe for the ATAD2 Bromodomain

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 flu...

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Published in:Angewandte Chemie International Edition 2016-09, Vol.55 (38), p.11382-11386
Main 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.
Format: Article
Language:English
Subjects:
bioisosteres
Cancer
conformation analysis
epigenetics
Fluorine
Lead
medicinal chemistry
Nanostructure
Permeability
Piperidine
Selectivity
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Summary: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. 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.
ISSN:1433-7851
1521-3773
1521-3773
DOI:10.1002/anie.201603928