PUBLICATION
Semisynthetic aurones inhibit tubulin polymerization at the colchicine-binding site and repress PC-3 tumor xenografts in nude mice and myc-induced T-ALL in zebrafish
- Authors
- Xie, Y., Kril, L.M., Yu, T., Zhang, W., Frasinyuk, M.S., Bondarenko, S.P., Kondratyuk, K.M., Hausman, E., Martin, Z.M., Wyrebek, P.P., Liu, X., Deaciuc, A., Dwoskin, L.P., Chen, J., Zhu, H., Zhan, C.G., Sviripa, V.M., Blackburn, J., Watt, D.S., Liu, C.
- ID
- ZDB-PUB-190425-11
- Date
- 2019
- Source
- Scientific Reports 9: 6439 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Benzofurans/chemical synthesis
- Benzofurans/chemistry
- Benzofurans/pharmacology
- Binding Sites
- Colchicine
- Humans
- Male
- Mice
- Mice, Nude
- Neoplasm Proteins/metabolism*
- PC-3 Cells
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/drug therapy
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/metabolism
- Precursor T-Cell Lymphoblastic Leukemia-Lymphoma*/pathology
- Prostatic Neoplasms*/drug therapy
- Prostatic Neoplasms*/metabolism
- Prostatic Neoplasms*/pathology
- Protein Multimerization/drug effects*
- Tubulin/metabolism*
- Xenograft Model Antitumor Assays
- Zebrafish/metabolism*
- PubMed
- 31015569 Full text @ Sci. Rep.
Citation
Xie, Y., Kril, L.M., Yu, T., Zhang, W., Frasinyuk, M.S., Bondarenko, S.P., Kondratyuk, K.M., Hausman, E., Martin, Z.M., Wyrebek, P.P., Liu, X., Deaciuc, A., Dwoskin, L.P., Chen, J., Zhu, H., Zhan, C.G., Sviripa, V.M., Blackburn, J., Watt, D.S., Liu, C. (2019) Semisynthetic aurones inhibit tubulin polymerization at the colchicine-binding site and repress PC-3 tumor xenografts in nude mice and myc-induced T-ALL in zebrafish. Scientific Reports. 9:6439.
Abstract
Structure-activity relationships (SAR) in the aurone pharmacophore identified heterocyclic variants of the (Z)-2-benzylidene-6-hydroxybenzofuran-3(2H)-one scaffold that possessed low nanomolar in vitro potency in cell proliferation assays using various cancer cell lines, in vivo potency in prostate cancer PC-3 xenograft and zebrafish models, selectivity for the colchicine-binding site on tubulin, and absence of appreciable toxicity. Among the leading, biologically active analogs were (Z)-2-((2-((1-ethyl-5-methoxy-1H-indol-3-yl)methylene)-3-oxo-2,3-dihydrobenzofuran-6-yl)oxy)acetonitrile (5a) and (Z)-6-((2,6-dichlorobenzyl)oxy)-2-(pyridin-4-ylmethylene)benzofuran-3(2H)-one (5b) that inhibited in vitro PC-3 prostate cancer cell proliferation with IC50 values below 100 nM. A xenograft study in nude mice using 10 mg/kg of 5a had no effect on mice weight, and aurone 5a did not inhibit, as desired, the human ether-à-go-go-related (hERG) potassium channel. Cell cycle arrest data, comparisons of the inhibition of cancer cell proliferation by aurones and known antineoplastic agents, and in vitro inhibition of tubulin polymerization indicated that aurone 5a disrupted tubulin dynamics. Based on molecular docking and confirmed by liquid chromatography-electrospray ionization-tandem mass spectrometry studies, aurone 5a targets the colchicine-binding site on tubulin. In addition to solid tumors, aurones 5a and 5b strongly inhibited in vitro a panel of human leukemia cancer cell lines and the in vivo myc-induced T cell acute lymphoblastic leukemia (T-ALL) in a zebrafish model.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping