{"doi":"10.1002/anie.202508427","title":"Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders","abstract":"Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease-related proteins. While molecular glue degraders exhibit drug-like properties, their discovery has traditionally been serendipitous and often requires post hoc rationalization. In this study, we demonstrate the rational, mechanism-guided design of molecular glue degraders using gluing moieties. Building on established principles, by appending a chemical gluing moiety to several small molecule inhibitors, we successfully transformed them into degraders, obviating the need for a specific E3 ubiquitin ligase recruiter. Specifically, we found that incorporating a hydrophobic aromatic ring or a double bond into a cyclin-dependent kinase 12 and 13 (CDK12/13) dual inhibitor enabled the recruitment of DNA damage-binding protein 1 (DDB1), thereby transforming a high-molecular-weight bivalent CDK12 degrader into a potent monovalent CDK12/13 molecular glue degrader. We also showcase that attaching a cysteine-reactive warhead to a bromodomain-containing protein 4 (BRD4) inhibitor converts it into a degrader by recruiting the DDB1 and CUL4-associated factor 16 (DCAF16) E3 ligase.","journal":"Angewandte Chemie International Edition","year":2025,"id":511325,"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":16,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9546,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1025172,"name":"Woong Sub Byun","orcid":"0000-0003-4676-3698","position":1,"is_corresponding":false},{"id":1034374,"name":"Zuzanna Kozicka","orcid":"0000-0003-0085-6565","position":2,"is_corresponding":false},{"id":299772,"name":"Katherine A. Donovan","orcid":"0000-0002-8539-5106","position":3,"is_corresponding":false},{"id":577164,"name":"Brendan G. Dwyer","orcid":"0000-0001-8593-4184","position":4,"is_corresponding":false},{"id":1369991,"name":"Abby M. Thornhill","orcid":null,"position":5,"is_corresponding":false},{"id":523798,"name":"Hannah M. Jones","orcid":"0000-0003-2711-4545","position":6,"is_corresponding":false},{"id":454450,"name":"Zixuan Jiang","orcid":"0000-0002-5291-6286","position":7,"is_corresponding":false},{"id":909583,"name":"Xijun Zhu","orcid":null,"position":8,"is_corresponding":false},{"id":262829,"name":"Eric S. Fischer","orcid":"0000-0001-7337-6306","position":9,"is_corresponding":false},{"id":636504,"name":"Nicolas H. Thomä","orcid":"0000-0003-2685-906X","position":10,"is_corresponding":false},{"id":226581,"name":"Nathanael S. Gray","orcid":"0000-0001-5354-7403","position":11,"is_corresponding":false},{"id":351360,"name":"Zhe Zhuang","orcid":"0000-0001-6679-0496","position":0,"is_corresponding":true}],"reference_count":36,"raw_metadata":null,"created_at":"2026-07-19T02:47:55.918021Z","pmid":"40626960","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":[]}