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To target both functions of CBP\/p300, two PROTAC\u2010based chemical degraders are developed by linking the CBP\/p300 catalytic inhibitor C646 and the Cereblon (CRBN) ligand thalidomide via polyethylene glycol\u2010based linkers. Both compounds exhibit submicromolar inhibition of CBP\/p300 and decrease their levels in the SU\u2010DHL\u201010 lymphoma cell line at low\u2010micromolar concentrations. Moreover, it is demonstrated that compound <jats:bold>1<\/jats:bold> recruits CBP\/p300 and CRBN in cells and acts as a bona fide PROTAC degrader of CBP\/p300 via the ubiquitin\u2010proteasome pathway. Finally, both compounds exhibit low\u2010micromolar antiproliferative activity in different lymphoma cell lines and are more potent than C646. 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