Discovery of Exceptionally Potent, Selective, and Efficacious PROTAC Degraders of CBP and p300 Proteins

The histone acetyltransferase CREB-binding protein (CBP)
and its
paralogue p300 protein are key transcriptional coactivators and attractive
cancer therapeutic targets. We describe herein our design, synthesis,
and extensive evaluation of exceptionally potent PROTAC degraders
of CBP/p300, exemplified by JET-209 (24). This compound,
JET-209, achieved a half-maximal degradation (DC50) value
of 0.05 nM for CBP and 0.2 nM for p300 with maximum degradation (Dmax) >95% for both proteins in the RS4;11
leukemia
cell line after 4 h of treatment. JET-209 achieved subnanomolar to
low nanomolar DC50 values in the inhibition of cell growth
in several representative acute leukemia cell lines and was much more
potent than CBP/p300 bromodomain and catalytic domain inhibitors.
JET-209 effectively inhibited tumor growth in xenograft tumor models
at tolerated dose schedules. JET-209 is a promising lead compound
for further evaluation and optimization toward the development of
a CBP/p300 degrader for the treatment of human cancers.