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

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

  • Adv Sci (Weinh). 2024 Jun 27:e2404668. doi: 10.1002/advs.202404668.
Pan Yan 1,  Gang Wang 2 3 4,  Minjian Huang 1 5,  Zhen Liu 1,  Chong Dai 1,  Ben Hu 6,  Meijia Gu 1,  Zixin Deng 7,  Ran Liu 7 8,  Xinghuan Wang 2 3 4,  Tiangang Liu 1 5 7 9
Affiliations

Affiliations

  • 1 Key Laboratory of Combinatorial Biosynthesis and Drug Discovery, Ministry of Education and School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
  • 2 Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 3 Department of Biological Repositories, Human Genetic Resource Preservation Center of Hubei Province, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 4 Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Wuhan University, Wuhan, 430071, China.
  • 5 Wuhan Hesheng Technology Co., Ltd, Wuhan, 430074, China.
  • 6 Precision Cancer Diagnostic Center, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China.
  • 7 State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, 200240, China.
  • 8 Key Laboratory of Quantitative Synthetic Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
  • 9 Department of Urology, Zhongnan Hospital of Wuhan University, School of Pharmaceutical Sciences, Wuhan University, Wuhan, 430071, China.
PMID: 38935027 DOI: 10.1002/advs.202404668
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.

Keywords

aglycone polyether; anti‐bladder cancer agents; combinatorial biosynthesis; drug design; structure‐activity relationships.

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