Discovery of Highly Potent and Efficient CBP/p300 Degraders with Strong <i>In Vivo</i> Antitumor Activity

The transcriptional coactivator cAMP response element binding protein (CREB)-binding protein (CBP) and its homologue p300 have emerged as attractive therapeutic targets for human cancers such as acute myeloid leukemia (AML). Herein, we report the design, synthesis, and biological evaluation of a series of cereblon (CRBN)-recruiting CBP/p300 proteolysis targeting chimeras (PROTACs) based on the inhibitor CCS1477. The representative compounds <b>14g</b> (XYD190) and <b>14h</b> (XYD198) potently inhibited the growth of AML cells with low nanomolar IC₅₀ values and effectively degraded CBP and p300 proteins in a concentration- and time-dependent manner. Mechanistic studies confirmed that <b>14g</b> and <b>14h</b> can selectively bind to CBP/p300 bromodomains and induce CBP and p300 degradation in bromodomain family proteins in a CRBN- and proteasome-dependent manner. <b>14g</b> and <b>14h</b> displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that <b>14g</b> and <b>14h</b> are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.