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

Abstract

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 14g (XYD190) and 14h (XYD198) potently inhibited the growth of AML cells with low nanomolar IC 50 values and effectively degraded CBP and p300 proteins in a concentration-and time-dependent manner. Mechanistic studies confirmed that 14g and 14h can selectively bind to CBP/p300 bromodomains and induce CBP and p300 degradation in bromodomain family proteins in a CRBN-and proteasome-dependent manner. 14g and 14h displayed remarkable antitumor efficacy in the MV4;11 xenograft model (TGI = 88% and 93%, respectively). Our findings demonstrated that 14g and 14h are useful lead compounds and deserve further optimization and activity evaluation for the treatment of human cancers.

Paralogue-Selective Degradation of the Lysine Acetyltransferase EP300

“…Our studies also emphasize the emerging spectrum of options for therapeutic EP300/CREBBP inhibition. In addition to the well-characterized HAT and BRD − ligands, there are now multiple potent dual degraders based on BRD ligands. − , JQAD-1 and MC-1 add to this collection by affording paralogue-specific degradation andin the case of MC-1, and possibly JQAD-1 as welldual HAT inhibition at high concentrations. In this latter scenario, MC-1 may be deployed as an augmented HAT inhibitor with an additional capability to degrade EP300.…”