RRC ID 69676
Author Kawano S, Ito K, Yahata K, Kira K, Abe T, Akagi T, Asano M, Iso K, Sato Y, Matsuura F, Ohashi I, Matsumoto Y, Isomura M, Sasaki T, Fukuyama T, Miyashita Y, Kaburagi Y, Yokoi A, Asano O, Owa T, Kishi Y.
Title A landmark in drug discovery based on complex natural product synthesis.
Journal Sci Rep
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.
Volume 9(1)
Pages 8656
Published 2019-6-17
DOI 10.1038/s41598-019-45001-9
PII 10.1038/s41598-019-45001-9
PMID 31209263
PMC PMC6572832
MeSH Actins / genetics Actins / metabolism Animals Antineoplastic Agents, Phytogenic / chemical synthesis* Antineoplastic Agents, Phytogenic / pharmacology Antineoplastic Combined Chemotherapy Protocols Biological Products / chemical synthesis Biological Products / pharmacology Breast Neoplasms / drug therapy* Breast Neoplasms / mortality Breast Neoplasms / pathology Cancer-Associated Fibroblasts / drug effects Cancer-Associated Fibroblasts / metabolism Cancer-Associated Fibroblasts / pathology Carcinoma, Squamous Cell / drug therapy* Carcinoma, Squamous Cell / mortality Carcinoma, Squamous Cell / pathology Cetuximab / pharmacology Drug Discovery Endothelial Cells / drug effects Endothelial Cells / metabolism Endothelial Cells / pathology Ethers, Cyclic / chemical synthesis* Ethers, Cyclic / pharmacology Female Gene Expression / drug effects Head and Neck Neoplasms / drug therapy* Head and Neck Neoplasms / mortality Head and Neck Neoplasms / pathology Humans Macrolides / chemical synthesis* Macrolides / pharmacology Mice Mice, Inbred BALB C Platelet Endothelial Cell Adhesion Molecule-1 / genetics Platelet Endothelial Cell Adhesion Molecule-1 / metabolism Survival Analysis Tubulin Modulators / chemical synthesis* Tubulin Modulators / pharmacology Tumor Burden / drug effects Xenograft Model Antitumor Assays
IF 3.998
Human and Animal Cells HSC-2(RCB1945)