halichondrin-b and Head-and-Neck-Neoplasms

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.

Topics: Actins; Animals; Antineoplastic Agents, Phytogenic; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Breast Neoplasms; Cancer-Associated Fibroblasts; Carcinoma, Squamous Cell; Cetuximab; Drug Discovery; Endothelial Cells; Ethers, Cyclic; Female; Gene Expression; Head and Neck Neoplasms; Humans; Macrolides; Mice; Mice, Inbred BALB C; Platelet Endothelial Cell Adhesion Molecule-1; Survival Analysis; Tubulin Modulators; Tumor Burden; Xenograft Model Antitumor Assays