4 research outputs found
Structure-based design of a bromodomain and extraterminal domain (BET) inhibitor selective for the N-terminal bromodomains that retains an anti-inflammatory and antiproliferative phenotype
The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects
Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the NTerminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype
Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors
ATAD2
is a bromodomain-containing protein whose overexpression is linked
to poor outcomes in a number of different cancer types. To date, no
potent and selective inhibitors of the bromodomain have been reported.
This article describes the structure-based optimization of a series
of naphthyridones from micromolar leads with no selectivity over the
BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold
BET selectivity
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