GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP)

Inhibition of the bromodomain of
the transcriptional regulator
CBP/P300 is an especially interesting new therapeutic approach in
oncology. We recently disclosed in vivo chemical tool 1 (GNE-272) for the bromodomain of CBP that was moderately potent
and selective over BRD4(1). In pursuit of a more potent and selective
CBP inhibitor, we used structure-based design. Constraining the aniline
of 1 into a tetrahydroquinoline motif maintained potency
and increased selectivity 2-fold. Structure–activity relationship
studies coupled with further structure-based design targeting the
LPF shelf, BC loop, and KAc regions allowed us to significantly increase
potency and selectivity, resulting in the identification of non-CNS
penetrant 19 (GNE-781, TR-FRET IC50 = 0.94
nM, BRET IC50 = 6.2 nM; BRD4(1) IC50 = 5100
nΜ) that maintained good in vivo PK properties in multiple species.
Compound 19 displays antitumor activity in an AML tumor
model and was also shown to decrease Foxp3 transcript levels in a
dose dependent manner.