{"doi":"10.1016/j.chembiol.2024.09.004","title":"Enhancer reprogramming underlies therapeutic utility of a SMARCA2 degrader in SMARCA4 mutant cancer","abstract":"Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes involved in cell proliferation. Furthermore, we identified YAP/TEADas key partners to SMARCA2 in driving growth of SMARCA4-mutant cells. Finally, we show that YD23 has potent tumor growth inhibitory activity in SMARCA4-mutant xenografts. These findings provide the mechanistic basis for development of SMARCA2 degraders as synthetic lethal therapeutics against SMARCA4-mutant lung cancers.","journal":"Cell chemical biology","year":2024,"id":431255,"datarank":0.4335557636844247,"base_score":2.8903717578961645,"endowment":2.8903717578961645,"self_citation_contribution":0.4335557636844247,"citation_network_contribution":0.0,"self_endowment_contribution":0.4335557636844247,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":17,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"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":952433,"name":"Nicholas Blazanin","orcid":"0009-0000-4171-1624","position":1,"is_corresponding":false},{"id":18350,"name":"Yuanxin Xi","orcid":"0000-0001-5509-2043","position":2,"is_corresponding":false},{"id":1235069,"name":"Yanyan Han","orcid":"0009-0000-5677-9875","position":3,"is_corresponding":false},{"id":1235571,"name":"Md Qudratullah","orcid":null,"position":4,"is_corresponding":false},{"id":1235572,"name":"Xiaobing Liang","orcid":null,"position":5,"is_corresponding":false},{"id":1235070,"name":"Yawen Wang","orcid":"0009-0001-6774-7948","position":6,"is_corresponding":false},{"id":572815,"name":"Poonam Pandey","orcid":"0000-0002-4251-4646","position":7,"is_corresponding":false},{"id":1235071,"name":"Hira Mazhar","orcid":"0000-0002-6400-5498","position":8,"is_corresponding":false},{"id":1235573,"name":"Truong Nguyen Lam","orcid":null,"position":9,"is_corresponding":false},{"id":68969,"name":"Anand K. Singh","orcid":"0000-0002-6855-3352","position":10,"is_corresponding":false},{"id":228165,"name":"Jing Wang","orcid":"0000-0002-5398-0802","position":11,"is_corresponding":false},{"id":1089635,"name":"Yonathan Lissanu","orcid":"0000-0003-1024-5303","position":12,"is_corresponding":false},{"id":1235570,"name":"Sasikumar Kotagiri","orcid":null,"position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:59:25.642507Z","pmid":"39378885","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":[]}