Development of C646‐Based Proteolysis Targeting Chimeras Degraders of the Lysine Acetyltransferases CBP and p300

The alteration of the lysine acetyltransferase activity and protein-protein interactions of the transcriptional co-activators CREB-binding protein (CBP) and p300 is linked to the development of both solid and hematological cancers. To target both functions of CBP/p300, two PROTAC-based chemical degraders are developed by linking the CBP/p300 catalytic inhibitor C646 and the Cereblon (CRBN) ligand thalidomide via polyethylene glycol-based linkers. Both compounds exhibit submicromolar inhibition of CBP/p300 and decrease their levels in the SU-DHL-10 lymphoma cell line at low-micromolar concentrations. Moreover, it is demonstrated that compound 1 recruits CBP/p300 and CRBN in cells and acts as a bona fide PROTAC degrader of CBP/p300 via the ubiquitin-proteasome pathway. Finally, both compounds exhibit low-micromolar antiproliferative activity in different lymphoma cell lines and are more potent than C646. Overall, it is demonstrated that the PROTAC strategy is a viable option for targeting CBP/p300 in lymphoma and identifies compound 1 as a promising chemical tool and lead compound for further studies.