TY - JOUR
T1 - Discovery of I-BRD9, a selective cell active chemical probe for bromodomain containing protein 9 inhibition
AU - Theodoulou, Natalie H.
AU - Bamborough, Paul
AU - Bannister, Andrew J.
AU - Becher, Isabelle
AU - Bit, Rino A.
AU - Che, Ka Hing
AU - Chung, Chun-wa
AU - Dittmann, Antje
AU - Drewes, Gerard
AU - Drewry, David H.
AU - Gordon, Laurie
AU - Grandi, Paola
AU - Leveridge, Melanie
AU - Lindon, Matthew
AU - Michon, Anne-Marie
AU - Molnar, Judit
AU - Robson, Samuel C.
AU - Tomkinson, Nicholas C. O.
AU - Kouzarides, Tony
AU - Prinjha, Rab K.
AU - Humphreys, Philip G.
PY - 2016/2/25
Y1 - 2016/2/25
N2 - Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.
AB - Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain “reader” modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.
U2 - 10.1021/acs.jmedchem.5b00256
DO - 10.1021/acs.jmedchem.5b00256
M3 - Article
SN - 0022-2623
VL - 59
SP - 1425
EP - 1439
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -