Abstract
Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.
MeSH terms
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Actins / genetics
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Actins / metabolism
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Animals
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Antineoplastic Agents, Phytogenic / chemical synthesis*
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Antineoplastic Agents, Phytogenic / pharmacology
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Antineoplastic Combined Chemotherapy Protocols
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Biological Products / chemical synthesis
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Biological Products / pharmacology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / mortality
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Breast Neoplasms / pathology
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Cancer-Associated Fibroblasts / drug effects
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Cancer-Associated Fibroblasts / metabolism
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Cancer-Associated Fibroblasts / pathology
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / mortality
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Carcinoma, Squamous Cell / pathology
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Cetuximab / pharmacology
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Drug Discovery
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism
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Endothelial Cells / pathology
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Ethers, Cyclic / chemical synthesis*
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Ethers, Cyclic / pharmacology
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Female
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Gene Expression / drug effects
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Head and Neck Neoplasms / drug therapy*
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Head and Neck Neoplasms / mortality
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Head and Neck Neoplasms / pathology
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Humans
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Macrolides / chemical synthesis*
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Macrolides / pharmacology
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Mice
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Mice, Inbred BALB C
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Platelet Endothelial Cell Adhesion Molecule-1 / genetics
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Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
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Survival Analysis
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Tubulin Modulators / chemical synthesis*
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Tubulin Modulators / pharmacology
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Tumor Burden / drug effects
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Xenograft Model Antitumor Assays
Substances
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ACTA2 protein, human
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Actins
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Antineoplastic Agents, Phytogenic
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Biological Products
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Ethers, Cyclic
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Macrolides
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PECAM1 protein, human
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Platelet Endothelial Cell Adhesion Molecule-1
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Tubulin Modulators
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halichondrin B
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halichondrin C
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Cetuximab