A Unique Approach to Design Potent and Selective Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP) Inhibitors

The
epigenetic regulator CBP/P300 presents a novel therapeutic
target for oncology. Previously, we disclosed the development of potent
and selective CBP bromodomain inhibitors by first identifying pharmacophores
that bind the KAc region and then building into the LPF shelf. Herein,
we report the “hybridization” of a variety of KAc-binding
fragments with a tetrahydroquinoline scaffold that makes optimal interactions
with the LPF shelf, imparting enhanced potency and selectivity to
the hybridized ligand. To demonstrate the utility of our hybridization
approach, two analogues containing unique Asn binders and the optimized
tetrahydroquinoline moiety were rapidly optimized to yield single-digit
nanomolar inhibitors of CBP with exquisite selectivity over BRD4(1)
and the broader bromodomain family.