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 has been the ready availability of high quality BET 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.<br/>P300/CBP-associated factor (PCAF) and general control nonderepressible 5 (GCN5) are multi-domain proteins containing a highly homologous bromodomain and are reported to have a role in the production of inflammatory cytokines. To (in)validate PCAF/GCN5 bromodomains as tractable and disease relevant targets, GSK embarked on a knowledge-based screen against the PCAF bromodomain. Deconstruction of an unselective hit to a highly efficient fragment was followed by structure guided optimisation to deliver GSK4027, a high quality PCAF/GCN5 bromodomain chemical probe. However, bromodomain inhibition alone with GSK4027 was unable to recapitulate the diminished inflammatory response of PCAF-deficient immune cells. The knowledge gained during the development of GSK4027 was used to generate the first bifunctional PCAF/GCN5 proteolysis targeting chimera (PROTAC) GSK699 which selectively degraded PCAF/GCN5 efficiently to demonstrate profound modulation of multiple inflammatory mediators in LPS-stimulated macrophages and dendritic cells.

Development of a PCAF/GCN5 bromodomain chemical probe/PROTAC toolbox and its utility in target (in)validation

2019 Fall National Meeting

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