Fragment-Based, Structure-Enabled Discovery of Novel Pyridones and Pyridone Macrocycles as Potent Bromodomain and Extra-Terminal Domain (BET) Family Bromodomain Inhibitors

Members
of the BET family of bromodomain containing proteins have been identified
as potential targets for blocking proliferation in a variety of cancer
cell lines. A two-dimensional NMR fragment screen for binders to the
bromodomains of BRD4 identified a phenyl­pyridazinone fragment
with a weak binding affinity (1, Ki = 160 μM). SAR investigation of fragment 1, aided by X-ray structure-based design, enabled the synthesis of
potent pyridone and macrocyclic pyridone inhibitors exhibiting single
digit nanomolar potency in both biochemical and cell based assays.
Advanced analogs in these series exhibited high oral exposures in
rodent PK studies and demonstrated significant tumor growth inhibition
efficacy in mouse flank xenograft models.