Jason Witherington, GSK
Written by Jackie Howard Tuesday, 08 May 2012 10:52
Bromodomains: A new class of epigenetic targets ripe for small molecule drug discovery
Bromodomain proteins constitute a large class of context-dependent epigenetic “readers” present in many developmental and transcriptional regulators. While the biological characterisation of many bromodomain containing proteins has advanced considerably, the therapeutic tractability of this protein family is hitherto undemonstrated. This presentation will describe the discovery and molecular characterisation of potent (nM) small molecule inhibitors that disrupt the function of the BET family of bromodomains (Brd2, 3, 4). Using a combination of phenotypic screening, chemoproteomics, biophysical and structural studies we reveal for the first time that the protein-protein interactions between bromodomains and chromatin can be antagonised effectively by selective small molecules that bind at the acetylated lysine recognition pocket and result in profound pharmacology. The development of a Bromodomain platform has enabled the breadth and depth of clinical opportunity in this novel target class to be appreciated.