Discovery and Characterizatlion of Small Molecule Inhibitors of the BET Family Bromodomains

作者：Chung Chun wa^*; Coste Herve; White Julia H; Mirguet Olivier; Wilde Jonathan; Gosmini Romain L; Delves Chris; Magny Sylvie M; Woodward Robert; Hughes Stephen A; Boursier Eric V; Flynn Helen; Bouillot Anne M; Bamborough Paul; Brusq Jean Marie G; Gellibert Francoise J; Jones Emma J; Riou Alizon M; Homes Paul; Martin Sandrine L; Uings Iain J; Toum Jerome; Clement Catherine A; Boullay Anne Benedicte; Grimley Rachel L; Blande Florence M; Prinjha Rab K

来源：Journal of Medicinal Chemistry, 2011, 54(11): 3827-3838.

DOI：10.1021/jm200108t

Epigenetic mechanisms of gene regulation have a profound role in normal development and disease processes. An integral part of this mechanism occurs through lysine acetylation of histone tails which are recognized by bromodomains. While the biological and structural characterization of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is only now becoming understood. This paper describes the discovery and molecular characterization of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromo domains (Brd2, Brd3, and Brd4). By using a combination of phenotypic screening, chemoproteomics, and biophysical studies, we have discovered that the protein protein interactions between bromodomains and acetylated histones can be antagonized by selective small molecules that bind at the acetylated lysine recognition pocket. X-ray crystal structures of compounds bound into bromodomains of Brd2 and Brd4 elucidate the molecular interactions of binding and explain the precisely defined stereochemistry required for activity.

• 出版日期2011-6-9