4A9N: N-Terminal Bromodomain Of Human Brd2 With N-Cyclopropyl-5-( 3,5-Dimethyl-1,2-Oxazol-4-Yl)-2-Methylbenzene-1- Sulfonamide

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.
PDB ID: 4A9NDownload
MMDB ID: 97140
PDB Deposition Date: 2011/11/26
Updated in MMDB: 2012/02
Experimental Method:
x-ray diffraction
Resolution: 1.85  Å
Source Organism:
Similar Structures:
Biological Unit for 4A9N: dimeric; determined by author and by software (PISA)
Molecular Components in 4A9N
Label Count Molecule
Proteins (2 molecules)
Bromodomain Containing 2(Gene symbol: BRD2)
Molecule annotation
Chemicals (10 molecules)
* Click molecule labels to explore molecular sequence information.

Citing MMDB