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

• Published in: Advanced science Vol. 11; no. 32; pp. e2404668 - n/a
• Main Authors: Yan, Pan, Wang, Gang, Huang, Minjian, Liu, Zhen, Dai, Chong, Hu, Ben, Gu, Meijia, Deng, Zixin, Liu, Ran, Wang, Xinghuan, Liu, Tiangang
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.08.2024; John Wiley and Sons Inc; Wiley
• Subjects: aglycone polyether; Animals; Antineoplastic Agents - pharmacology; anti‐bladder cancer agents; Bioinformatics; Biosynthesis; Bladder cancer; Breast cancer; Cancer therapies; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; combinatorial biosynthesis; Disease Models, Animal; drug design; Ethers - chemistry; Ethers - pharmacology; FDA approval; Genes; Humans; Metastasis; Mice; Stem cells; Structure-Activity Relationship; structure‐activity relationships; Sugar; Toxicity; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; combinatorial biosynthesis; aglycone polyether; anti‐bladder cancer agents; drug design; structure‐activity relationships
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202404668

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. Based on the structure‐activity relationship of aglycone polyethers and the biosynthetic mechanisms of lenoremycin and endusamycin, new biosynthetic pathways are rationally designed, resulting in the creation of a novel C11‐glycosylated polyether, End‐16. In mouse models, End‐16 exhibits superior inhibitory activity and fewer side effects against bladder cancer compared to the frontline clinical drug cisplatin.