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

ChemMedChem. 2025 Jun 17;20(12):e202400792. doi: 10.1002/cmdc.202400792. Epub 2025 Apr 11.

Abstract

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.

Keywords: acetylation; epigenetics; lymphoma; proteolysis targeting chimeras; targeted degradation.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Antineoplastic Agents* / chemical synthesis
  • Antineoplastic Agents* / chemistry
  • Antineoplastic Agents* / pharmacology
  • Benzoates
  • CREB-Binding Protein* / antagonists & inhibitors
  • CREB-Binding Protein* / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Development*
  • Drug Screening Assays, Antitumor
  • E1A-Associated p300 Protein* / antagonists & inhibitors
  • E1A-Associated p300 Protein* / metabolism
  • Enzyme Inhibitors* / chemical synthesis
  • Enzyme Inhibitors* / chemistry
  • Enzyme Inhibitors* / pharmacology
  • Humans
  • Molecular Structure
  • Nitrobenzenes
  • Proteolysis / drug effects
  • Proteolysis Targeting Chimera
  • Pyrazolones
  • Structure-Activity Relationship
  • Thalidomide* / analogs & derivatives
  • Thalidomide* / chemical synthesis
  • Thalidomide* / chemistry
  • Thalidomide* / pharmacology
  • Ubiquitin-Protein Ligases
  • p300-CBP Transcription Factors* / antagonists & inhibitors
  • p300-CBP Transcription Factors* / metabolism

Substances

  • Thalidomide
  • 4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid
  • Antineoplastic Agents
  • p300-CBP Transcription Factors
  • E1A-Associated p300 Protein
  • CREB-Binding Protein
  • CRBN protein, human
  • EP300 protein, human
  • Enzyme Inhibitors
  • CREBBP protein, human
  • Proteolysis Targeting Chimera
  • Nitrobenzenes
  • Benzoates
  • Pyrazolones
  • Ubiquitin-Protein Ligases
  • Adaptor Proteins, Signal Transducing