{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Cheng-Sanchez I"],"funding":["Swiss National Science Foundation","Krebsliga Schweiz"],"pagination":["355-361"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10945562"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["15(3)"],"pubmed_abstract":["Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that simultaneously bind an E3 ligase and a protein of interest, inducing degradation of the latter via the ubiquitin-proteasome system. Here we present the development of degraders targeting CREB-binding protein (CBP) and E1A-associated protein (EP300)-two homologous multidomain enzymes crucial for enhancer-mediated transcription. Our PROTAC campaign focused on CPI-1612, a reported inhibitor of the histone acetyltransferase (HAT) domain of these two proteins. A novel asymmetric synthesis of this ligand was devised, while PROTAC-SAR was explored by measuring degradation, target engagement, and ternary complex formation <i>in cellulo</i>. Our study demonstrates that engagement of Cereblon (CRBN) and a sufficiently long linker between the E3 and CBP/EP300 binders (≥21 atoms) are required for PROTAC-mediated degradation using CPI-1612 resulting in a new active PROTAC <b>dCE-1</b>. Lessons learned from this campaign, particularly the importance of cell-based assays to understand the reasons underlying PROTAC performance, are likely applicable to other targets to assist the development of degraders."],"journal":["ACS medicinal chemistry letters"],"pubmed_title":["Discovery and Characterization of Active CBP/EP300 Degraders Targeting the HAT Domain."],"pmcid":["PMC10945562"],"funding_grant_id":["180345","KFS-4585-08-2018","Sinergia Grant CRSII5_180345/1"],"pubmed_authors":["Kirillova MS","Nevado C","Gossele KA","Cheng-Sanchez I","Palaferri L"],"additional_accession":[]},"is_claimable":false,"name":"Discovery and Characterization of Active CBP/EP300 Degraders Targeting the HAT Domain.","description":"Proteolysis Targeting Chimeras (PROTACs) are bifunctional molecules that simultaneously bind an E3 ligase and a protein of interest, inducing degradation of the latter via the ubiquitin-proteasome system. Here we present the development of degraders targeting CREB-binding protein (CBP) and E1A-associated protein (EP300)-two homologous multidomain enzymes crucial for enhancer-mediated transcription. Our PROTAC campaign focused on CPI-1612, a reported inhibitor of the histone acetyltransferase (HAT) domain of these two proteins. A novel asymmetric synthesis of this ligand was devised, while PROTAC-SAR was explored by measuring degradation, target engagement, and ternary complex formation <i>in cellulo</i>. Our study demonstrates that engagement of Cereblon (CRBN) and a sufficiently long linker between the E3 and CBP/EP300 binders (≥21 atoms) are required for PROTAC-mediated degradation using CPI-1612 resulting in a new active PROTAC <b>dCE-1</b>. Lessons learned from this campaign, particularly the importance of cell-based assays to understand the reasons underlying PROTAC performance, are likely applicable to other targets to assist the development of degraders.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-06-02T18:07:03.567Z","creation":"2025-04-04T00:26:31.722Z"},"accession":"S-EPMC10945562","cross_references":{"pubmed":["38505842"],"doi":["10.1021/acsmedchemlett.3c00490"]}}