Abstract

The Development Of non-BET Bromodomain Chemical Probes

Phil Humphreys, Senior Scientific Investigator, GlaxoSmithKline

Bromodomains have emerged as an exciting target class for drug discovery over the past decade. Research has primarily focused on the bromodomain and extra terminal (BET) family of bromodomains, which has led to the development of multiple small molecule inhibitors and an increasing number of clinical assets. Central to this flurry of research in the BET field has been the ready availability of high quality small molecule chemical probes, in particular I-BET762 and (+)-JQ1. However, the BET family represents only eight reader domains of the bromodomain phylogenetic tree and the therapeutic potential of the remaining 53 bromodomains is comparatively less explored. The development of non-BET bromodomain chemical probes will allow the community to gain a better understanding of their biology and potentially, help to identify and validate new targets for drug discovery. To this end, research in the Epigenetics Discovery Performance Unit within GlaxoSmithKline has led to the identification of a number of high quality chemical probes for non-BET bromodomains. This lecture will communicate our work in developing small molecule bromodomain chemical probes, in particular for the PCAF/GCN5 bromodomain.