Abstract

Discovery Of Low Nanomolar, Selective And Cell Permeable ATAD2 Bromodomain Inhibitors

Emmanuel Demont, Director, GlaxoSmithKline

Over expression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. Generation of potent and highly selective small molecule ATAD2 inhibitors was deemed to be essential to understanding the therapeutic potential of the bromodomain. We will describe our medicinal chemistry effort, which led to the identification of the first reported chemical probe for this bromodomain. In particular, we will highlight how we managed to gain selectivity against the BET family of proteins. This is particularly important as the profound biological effects associated with BET inhibition complicate interpretation of phenotypes observed with unselective inhibitors. We will also demonstrate how the use of bioisosteres had a dramatic impact on the permeability of our inhibitors. The profile of our probe will be highlighted as well as early phenotypic data.