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 (D_max) >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.