Abstract: The histone acetyltransferase CREB-binding protein (CBP) and its paralogue p300 protein are key transcriptional co-activators and attractive therapeutic targets for human prostate cancer and other types of human cancers. Development of highly potent and orally active small-molecule degraders of CBP and p300 proteins represents a promising new therapeutic strategy. Our preliminary data demonstrate that our designed degraders are highly effective in inducing rapid and complete degradation of both CBP and p300 proteins in tumor cells at sub-xnanomolar concentrations and >100-times more potent in in inhibition of cell growth than CBP/p300 inhibitors. Our optimized CBP/p300 degraders achieve excellent pharmacokinetics and oral bioavailability in mice. Oral administration of our optimized CBP/p300 degrader strongly inhibits tumor growth in animal models of human cancer at well-tolerated dose-schedules. Collectively, our preliminary data provide compelling data to support the further evaluation, optimization and development of orally active CBP/p300 degraders as a new anticancer therapy.