DataVXAdvanced SciencePaper
journal article·2024-08Open access

Combinatorial Biosynthesis Creates a Novel Aglycone Polyether with High Potency and Low Side Effects Against Bladder Cancer

Pan Yan, Gang Wang, Minjian Huang, Zhen Liu, Chong Dai, Ben Hu, Meijia Gu, Zixin Deng, Ran Liu, Xinghuan Wang, Tiangang Liu

Advanced Science· Volume 11· Issue 32
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Abstract

Abstract 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‐activity 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‐polyketide 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‐16, which demonstrates significant potential for treating bladder cancer (BLCA). End‐16 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‐16 exhibits superior inhibitory activity and fewer side effects against BLCA compared to the frontline anti‐BLCA 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.
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Research context

OpenAlex topics: Microbial Natural Products and Biosynthesis · Cancer therapeutics and mechanisms · Histone Deacetylase Inhibitors Research

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Key Laboratory of Combinatorial Biosynthesis and Drug Discovery Ministry of Education and School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China

Department of Urology Zhongnan Hospital of Wuhan University Wuhan 430071 China

Department of Biological Repositories Human Genetic Resource Preservation Center of Hubei Province Zhongnan Hospital of Wuhan University Wuhan 430071 China

Medical Research Institute Frontier Science Center of Immunology and Metabolism Wuhan University Wuhan 430071 China

Wuhan Hesheng Technology Co., Ltd Wuhan 430074 China

Precision Cancer Diagnostic Center Zhongnan Hospital of Wuhan University Wuhan 430071 China

State Key Laboratory of Microbial Metabolism School of Life Sciences and Biotechnology Shanghai Jiao Tong University Shanghai 200240 China

Key Laboratory of Quantitative Synthetic Biology Shenzhen Institute of Synthetic Biology Shenzhen Institutes of Advanced Technology Chinese Academy of Sciences Shenzhen 518055 China

Department of Urology Zhongnan Hospital of Wuhan University School of Pharmaceutical Sciences Wuhan University Wuhan 430071 China

Funding

National Key Research and Development Program of China · Fundamental Research Funds for the Central Universities · National Natural Science Foundation of China

References (29)

Show source-provided references
1. 10.1351/pac19865805070110.1351/pac198658050701 ↗
2. 10.1038/nrd338910.1038/nrd3389 ↗
3. 10.1016/j.cell.2009.06.03410.1016/j.cell.2009.06.034 ↗
4. 10.1038/nchem.277810.1038/nchem.2778 ↗
5. 10.1021/acsptsci.8b0000710.1021/acsptsci.8b00007 ↗
6. 10.1038/s41429-022-00571-110.1038/s41429-022-00571-1 ↗
7. 10.3322/caac.2166010.3322/caac.21660 ↗
8. 10.1001/jama.2020.1759810.1001/jama.2020.17598 ↗
9. 10.1016/j.ctrv.2020.10207210.1016/j.ctrv.2020.102072 ↗
10. 10.1038/s41389-017-0013-710.1038/s41389-017-0013-7 ↗
11. 10.1016/S1074-5521(03)00092-910.1016/S1074-5521(03)00092-9 ↗
12. 10.1093/nar/gkx124910.1093/nar/gkx1249 ↗
13. 10.1038/nature1086510.1038/nature10865 ↗
14. 10.1021/ja301386g10.1021/ja301386g ↗
15. 10.1016/j.chembiol.2006.07.00610.1016/j.chembiol.2006.07.006 ↗
16. 10.1016/j.chembiol.2008.04.00610.1016/j.chembiol.2008.04.006 ↗
17. 10.7164/antibiotics.37.81310.7164/antibiotics.37.813 ↗
18. 10.1038/s41580-021-00404-310.1038/s41580-021-00404-3 ↗
19. 10.1016/j.phymed.2024.15573410.1016/j.phymed.2024.155734 ↗
20. 10.1038/s41401-020-0404-810.1038/s41401-020-0404-8 ↗
21. 10.1038/s41580-022-00530-610.1038/s41580-022-00530-6 ↗
22. 10.1016/j.tcb.2018.12.00110.1016/j.tcb.2018.12.001 ↗
23. 10.1038/s41580-018-0080-410.1038/s41580-018-0080-4 ↗
24. 10.3390/molecules2704137210.3390/molecules27041372 ↗
25. 10.3390/nano1002019010.3390/nano10020190 ↗
26. 10.1093/nar/gkx124910.1093/nar/gkx1249 ↗
27. 10.1038/nprot.2016.05410.1038/nprot.2016.054 ↗
28. 10.1016/j.synbio.2016.07.00210.1016/j.synbio.2016.07.002 ↗
29. 10.1016/j.ymben.2013.07.00610.1016/j.ymben.2013.07.006 ↗