Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors

Overexpression 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. The absence of any potent, selective
inhibitors limits clear understanding of the therapeutic potential
of the bromodomain. Here, we describe the discovery of a hit from
a fragment-based targeted array. Optimization of this produced the
first known micromolar inhibitors of the ATAD2 bromodomain.