{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T14:42:13Z","timestamp":1759761733536,"version":"build-2065373602"},"reference-count":29,"publisher":"Wiley","issue":"32","license":[{"start":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T00:00:00Z","timestamp":1719446400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2018YFA0900400"],"award-info":[{"award-number":["2018YFA0900400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["2042022dx0003"],"award-info":[{"award-number":["2042022dx0003"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32100053"],"award-info":[{"award-number":["32100053"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Polyethers play a crucial role in the development of anticancer drugs. To enhance the anticancer efficacy and reduce the toxicity of these compounds, thereby advancing their application in cancer treatment, herein, guided by the structure\u2010activity relationships of aglycone polyethers, novel aglycone polyethers are rationally redesigned with potentially improved efficacy and reduced toxicity against tumors. To realize the biosynthesis of the novel aglycone polyethers, the gene clusters and the post\u2010polyketide synthase tailoring pathways for aglycone polyethers endusamycin and lenoremycin are identified and subjected to combinatorial biosynthesis studies, resulting in the creation of a novel aglycone polyether termed End\u201016, which demonstrates significant potential for treating bladder cancer (BLCA). End\u201016 demonstrates the ability to suppress the proliferation, migration, invasion, and cellular protrusions formation of BLCA cells, as well as induce cell cycle arrest in the G1 phase in vitro. Notably, End\u201016 exhibits superior inhibitory activity and fewer side effects against BLCA compared to the frontline anti\u2010BLCA drug cisplatin in vivo, thereby warranting further preclinical studies. This study highlights the significant potential of integrating combinatorial biosynthesis strategies with rational design to create unnatural products with enhanced pharmacological properties.<\/jats:p>","DOI":"10.1002\/advs.202404668","type":"journal-article","created":{"date-parts":[[2024,6,27]],"date-time":"2024-06-27T14:23:27Z","timestamp":1719498207000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Combinatorial Biosynthesis Creates a Novel Aglycone Polyether with High Potency and Low Side Effects Against Bladder Cancer"],"prefix":"10.1002","volume":"11","author":[{"given":"Pan","family":"Yan","sequence":"first","affiliation":[{"name":"Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education and School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology Zhongnan Hospital of Wuhan University Wuhan 430071 China"},{"name":"Department of Biological Repositories Human Genetic Resource Preservation Center of Hubei Province Zhongnan Hospital of Wuhan University Wuhan 430071 China"},{"name":"Medical Research Institute Frontier Science Center of Immunology and Metabolism Wuhan University Wuhan 430071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minjian","family":"Huang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education and School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China"},{"name":"Wuhan Hesheng Technology Co., Ltd  Wuhan 430074 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education and School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chong","family":"Dai","sequence":"additional","affiliation":[{"name":"Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education and School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ben","family":"Hu","sequence":"additional","affiliation":[{"name":"Precision Cancer Diagnostic Center Zhongnan Hospital of Wuhan University Wuhan 430071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meijia","family":"Gu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education and School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zixin","family":"Deng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism School of Life Sciences and Biotechnology Shanghai Jiao Tong University Shanghai 200240 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9605-231X","authenticated-orcid":false,"given":"Ran","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Microbial Metabolism School of Life Sciences and Biotechnology Shanghai Jiao Tong University Shanghai 200240 China"},{"name":"Key Laboratory of Quantitative Synthetic Biology Shenzhen Institute of Synthetic Biology Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences  Shenzhen 518055 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3497-0024","authenticated-orcid":false,"given":"Xinghuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology Zhongnan Hospital of Wuhan University Wuhan 430071 China"},{"name":"Department of Biological Repositories Human Genetic Resource Preservation Center of Hubei Province Zhongnan Hospital of Wuhan University Wuhan 430071 China"},{"name":"Medical Research Institute Frontier Science Center of Immunology and Metabolism Wuhan University Wuhan 430071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8087-0345","authenticated-orcid":false,"given":"Tiangang","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education and School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China"},{"name":"Wuhan Hesheng Technology Co., Ltd  Wuhan 430074 China"},{"name":"State Key Laboratory of Microbial Metabolism School of Life Sciences and Biotechnology Shanghai Jiao Tong University Shanghai 200240 China"},{"name":"Department of Urology Zhongnan Hospital of Wuhan University School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,6,27]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1351\/pac198658050701"},{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3389"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2009.06.034"},{"key":"e_1_2_8_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchem.2778"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsptsci.8b00007"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41429-022-00571-1"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2020.17598"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2020.102072"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41389-017-0013-7"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-5521(03)00092-9"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1249"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature10865"},{"key":"e_1_2_8_11_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja301386g"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2006.07.006"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2008.04.006"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.7164\/antibiotics.37.813"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-021-00404-3"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155734"},{"key":"e_1_2_8_15_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-020-0404-8"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-022-00530-6"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2018.12.001"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-018-0080-4"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27041372"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.3390\/nano10020190"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1249"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2016.054"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.synbio.2016.07.002"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymben.2013.07.006"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202404668","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T14:05:01Z","timestamp":1759759501000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202404668"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,6,27]]},"references-count":29,"journal-issue":{"issue":"32","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1002\/advs.202404668"],"URL":"https:\/\/doi.org\/10.1002\/advs.202404668","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"type":"print","value":"2198-3844"},{"type":"electronic","value":"2198-3844"}],"subject":[],"published":{"date-parts":[[2024,6,27]]},"assertion":[{"value":"2024-05-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-06-27","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2404668"}}