Development of C646-based PROTAC Degraders of the Lysine Acetyltransferases CBP and p300.

Abstract

The alteration of the lysine acetyltransferase activity and protein-protein interactions of the transcriptional co-activators CBP and p300 is linked to the development of both solid and haematological cancers. To target both functions of CBP/p300, we developed two PROTAC-based chemical degraders by linking the CBP/p300 catalytic inhibitor C646 and the CRBN ligand thalidomide via PEG-based linkers. Both compounds exhibited submicromolar inhibition of CBP/p300 and decreased their levels in the SU-DHL-10 lymphoma cell line at low-micromolar concentrations. Moreover, we 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 exhibited low-micromolar antiproliferative activity in different lymphoma cell lines and were more potent than C646. Overall, we demonstrated that the PROTAC strategy is a viable option for targeting CBP/p300 in lymphoma and identified compound 1 as a promising chemical tool and lead compound for further studies.