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A Chemical Probe for the ATAD2 Bromodomain
Author(s) -
Bamborough Paul,
Chung Chunwa,
Demont Emmanuel H.,
Furze Rebecca C.,
Bannister Andrew J.,
Che Ka Hing,
Diallo Hawa,
Douault Clement,
Grandi Paola,
Kouzarides Tony,
Michon AnneMarie,
Mitchell Darren J.,
Prinjha Rab K.,
Rau Christina,
Robson Samuel,
Sheppard Robert J.,
Upton Richard,
Watson Robert J.
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201603928
Subject(s) - druggability , bromodomain , isostere , chemistry , selectivity , piperidine , combinatorial chemistry , sulfone , stereochemistry , biochemistry , organic chemistry , dna , gene , histone , catalysis
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 CF 2 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.