National Center for
4A9N: N-Terminal Bromodomain Of Human Brd2 With N-Cyclopropyl-5-( 3,5-Dimethyl-1,2-Oxazol-4-Yl)-2-Methylbenzene-1- Sulfonamide
Fragment-based discovery of bromodomain inhibitors part 2: optimization of phenylisoxazole sulfonamides
J. Med. Chem. (2012) 55 p.587-596
Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this protein-protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization.