Abstract

Bromodomain Drug Discovery

Andrea Cochran, Principal Scientist, Early Discovery Biochemistry, Genentech

Bromodomains are “reader” modules that recognize acetylated lysine in histones and other proteins. Much recent attention has focused on BET (bromo and extra-terminal domain)-class bromodomain proteins such as BRD4, and several BET inhibitors are now in human clinical trials. Bromodomains are present in dozens of human proteins other than the four BET proteins, yet the functions of these non-BET bromodomains and their potential as therapeutic targets are much less understood. I will present a discovery platform for chemical probes targeting non-BET bromodomains that resulted from a collaboration between Genentech and Constellation Pharmaceuticals. In addition, we have conducted peptide array screens of non-histone acetylated peptides taken from transcription factors and other nuclear proteins. These screens reveal that many non-histone proteins are candidate binding partners for bromodomains and that bromodomains differ widely in both the number and identities of peptides recognized. These candidate interactors suggest specific pathways in which small-molecule chemical probes might be expected to show effects, and this approach can complement unbiased phenotypic screening as a way to evaluate both probes and targets.