{"doi":"10.1101/2024.05.03.592353","title":"Paralogue-selective degradation of the lysine acetyltransferase EP300","abstract":"The transcriptional coactivators EP300 and CREBBP are critical regulators of gene expression that share high sequence identity but exhibit non-redundant functions in basal and pathological contexts. Here, we report the development of a bifunctional small molecule, MC-1, capable of selectively degrading EP300 over CREBBP. Using a potent aminopyridine-based inhibitor of the EP300/CREBBP catalytic domain in combination with a VHL ligand, we demonstrate that MC-1 preferentially degrades EP300 in a proteasome-dependent manner. Mechanistic studies reveal that selective degradation cannot be predicted solely by target engagement or ternary complex formation, suggesting additional factors govern paralogue-specific degradation. MC-1 inhibits cell proliferation in a subset of cancer cell lines and provides a new tool to investigate the non-catalytic functions of EP300 and CREBBP. Our findings expand the repertoire of EP300/CREBBP-targeting chemical probes and offer insights into the determinants of selective degradation of highly homologous proteins.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":488455,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":676555,"name":"McKenna C. Crawford","orcid":"0000-0002-3274-1255","position":1,"is_corresponding":false},{"id":860722,"name":"Ying Xiong","orcid":"0009-0009-8835-202X","position":2,"is_corresponding":false},{"id":706475,"name":"Anver Basha Shaik","orcid":"0000-0001-9894-5544","position":3,"is_corresponding":false},{"id":511610,"name":"Kiall F. Suazo","orcid":"0000-0002-0803-8332","position":4,"is_corresponding":false},{"id":1333473,"name":"Manini S. Penkalapati","orcid":null,"position":5,"is_corresponding":false},{"id":1277072,"name":"Joycelyn H. Williams","orcid":null,"position":6,"is_corresponding":false},{"id":340924,"name":"Thorkell Andressen","orcid":null,"position":7,"is_corresponding":false},{"id":663568,"name":"Rolf E. Swenson","orcid":"0000-0001-7804-7202","position":8,"is_corresponding":false},{"id":232494,"name":"Jordan L. Meier","orcid":"0000-0002-0537-7101","position":9,"is_corresponding":false},{"id":1276644,"name":"Xuemin Chen","orcid":"0000-0002-0860-4365","position":0,"is_corresponding":true}],"reference_count":40,"raw_metadata":null,"created_at":"2026-07-19T02:08:19.655720Z","pmid":"38746397","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}