A landmark in drug discovery based on complex natural product synthesis.
Actins
/ genetics
Animals
Antineoplastic Agents, Phytogenic
/ chemical synthesis
Antineoplastic Combined Chemotherapy Protocols
Biological Products
/ chemical synthesis
Breast Neoplasms
/ drug therapy
Cancer-Associated Fibroblasts
/ drug effects
Carcinoma, Squamous Cell
/ drug therapy
Cetuximab
/ pharmacology
Drug Discovery
Endothelial Cells
/ drug effects
Ethers, Cyclic
/ chemical synthesis
Female
Gene Expression
/ drug effects
Head and Neck Neoplasms
/ drug therapy
Humans
Macrolides
/ chemical synthesis
Mice
Mice, Inbred BALB C
Platelet Endothelial Cell Adhesion Molecule-1
/ genetics
Survival Analysis
Tubulin Modulators
/ chemical synthesis
Tumor Burden
/ drug effects
Xenograft Model Antitumor Assays
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
17 06 2019
17 06 2019
Historique:
received:
08
01
2019
accepted:
29
05
2019
entrez:
19
6
2019
pubmed:
19
6
2019
medline:
21
10
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31209263
doi: 10.1038/s41598-019-45001-9
pii: 10.1038/s41598-019-45001-9
pmc: PMC6572832
doi:
Substances chimiques
ACTA2 protein, human
0
Actins
0
Antineoplastic Agents, Phytogenic
0
Biological Products
0
Ethers, Cyclic
0
Macrolides
0
PECAM1 protein, human
0
Platelet Endothelial Cell Adhesion Molecule-1
0
Tubulin Modulators
0
halichondrin B
269R6PFM59
halichondrin C
9482880YOP
Cetuximab
PQX0D8J21J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
8656Références
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