Playing the System: Finding Selective Chemical Probes for Bromodomain Epigenetic Readers
Paul Bamborough,
Computational Chemistry Section Head,
GlaxoSmithKline
Recent developments have demonstrated the tractability of the BET family of bromodomains to druglike small-molecule inhibitors. As these progress into the clinic, this success has promoted interest in the other members of this target class, which are generally much less intensively studied and whose biological function is less well understood. Chemical probes of these bromodomains would be of great interest as tools to understand their importance in disease. These modules share a common function of acetyl-lysine peptide binding using conserved structural motifs, leading to recurring themes in inhibitor discovery and opportunities to target the family in a more systematic way. Some of the challenges and approaches used to identify potent and highly selective tool compounds within the bromodomain system will be discussed from a structural and medicinal chemistry perspective. Examples will span a range of tractability, from high (such as BRPF1, bromodomain and PHD finger-containing protein 1) to low ligandability (ATAD2, ATPase family, AAA domain containing protein 2).
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