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

• DOI: 10.1002/cmdc.202400792
• Publication Date: 2025-04-01T08:24:30Z
• Authors: Francesco Fiorentino; Filippo Spriano; Daniela Tomaselli; Giorgia Risi; Emanuele Fabbrizi; Valeria Pecci; Simona Nanni; Francesco Bertoni; Dante Rotili; Antonello Mai

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.