Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors

ATAD2 is a cancer-associated
protein whose bromodomain has been
described as among the least druggable of its class. In our recent
disclosure of the first chemical probe against this bromodomain, GSK8814
(6), we described the use of a conformationally constrained
methoxy piperidine to gain selectivity over the BET bromodomains.
Here we describe an orthogonal conformational restriction strategy
of the piperidine ring to give potent and selective tropane inhibitors
and show structural insights into why this was more challenging than
expected. Greater understanding of why different rational approaches
succeeded or failed should help in the future design of selectivity
in the bromodomain family.