{"doi":"10.1021/acschembio.2c00902","title":"Design of Class I/IV Bromodomain-Targeting Degraders for Chromatin Remodeling Complexes","abstract":"Targeted protein degradation is an emerging technology that can be used for modulating the activity of epigenetic protein targets. Among bromodomain-containing proteins, a number of degraders for the BET family have been developed, while non-BET bromodomains remain underexplored. Several of these proteins are subunits in chromatin remodeling complexes often associated with oncogenic roles. Here, we describe the design of class I (BPTF and CECR2) and IV (BRD9) bromodomain-targeting degraders based on two scaffolds derived from pyridazinone and pyrimidine-based heterocycles. We evaluate various exit vectors and linkers to identify analogues that demonstrate selectivity within these families. We further use an in-cell NanoBRET assay to demonstrate that these heterobifunctional molecules are cell-permeable, form ternary complexes, and can degrade nanoluciferase-bromodomain fusions. As a first example of a CECR2 degrader, we observe that our pyrimidine-based analogues degrade endogenous CECR2 while showing a smaller effect on BPTF levels. The pyridazinone-based compounds did not degrade BPTF when observed through Western blotting, further supporting a more challenging target for degradation and a goal for future optimization.","journal":"ACS Chemical Biology","year":2023,"id":349582,"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":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9562,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1010076,"name":"Jeff P. Costello","orcid":null,"position":1,"is_corresponding":false},{"id":1093140,"name":"Yao Li","orcid":"0000-0001-7666-8777","position":2,"is_corresponding":false},{"id":453576,"name":"Jennifer R. Kimbrough","orcid":"0000-0003-0221-3088","position":3,"is_corresponding":false},{"id":629050,"name":"Marisa Actis","orcid":null,"position":4,"is_corresponding":false},{"id":381383,"name":"Zoran Ranković","orcid":"0000-0001-6866-4290","position":5,"is_corresponding":false},{"id":110497,"name":"Qin Yan","orcid":"0000-0003-4077-453X","position":6,"is_corresponding":false},{"id":118141,"name":"William C. K. Pomerantz","orcid":"0000-0002-0163-4078","position":7,"is_corresponding":false},{"id":395406,"name":"Huda Zahid","orcid":"0000-0003-1711-7048","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-19T01:12:19.059218Z","pmid":"37260298","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":[]}