PUBLICATION
Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors
- Authors
- Yao, Y., Huang, T., Wang, Y., Wang, L., Feng, S., Cheng, W., Yang, L., Duan, Y.
- ID
- ZDB-PUB-220204-1
- Date
- 2022
- Source
- Journal of enzyme inhibition and medicinal chemistry 37: 652-665 (Journal)
- Registered Authors
- Keywords
- Leukaemia, anti-angiogenesis, tubulin, zebrafish
- MeSH Terms
-
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/chemistry
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Antineoplastic Agents/chemical synthesis
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology*
- Apoptosis/drug effects
- Binding Sites/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Colchicine/antagonists & inhibitors*
- Colchicine/metabolism
- Dose-Response Relationship, Drug
- Drug Screening Assays, Antitumor
- Humans
- Indoles/chemical synthesis
- Indoles/chemistry
- Indoles/pharmacology*
- Models, Molecular
- Molecular Structure
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/metabolism
- Neoplasms, Experimental/pathology
- Neovascularization, Pathologic/drug therapy*
- Neovascularization, Pathologic/metabolism
- Neovascularization, Pathologic/pathology
- Structure-Activity Relationship
- Tubulin/metabolism
- Tubulin Modulators/chemical synthesis
- Tubulin Modulators/chemistry
- Tubulin Modulators/pharmacology*
- Zebrafish
- PubMed
- 35109719 Full text @ J Enzyme Inhib Med Chem
Citation
Yao, Y., Huang, T., Wang, Y., Wang, L., Feng, S., Cheng, W., Yang, L., Duan, Y. (2022) Angiogenesis and anti-leukaemia activity of novel indole derivatives as potent colchicine binding site inhibitors. Journal of enzyme inhibition and medicinal chemistry. 37:652-665.
Abstract
The screened compound DYT-1 from our in-house library was taken as a lead (inhibiting tubulin polymerisation: IC50=25.6 µM, anti-angiogenesis in Zebrafish: IC50=38.4 µM, anti-proliferation against K562 and Jurkat: IC50=6.2 and 7.9 µM, respectively). Further investigation of medicinal chemistry conditions yielded compound 29e (inhibiting tubulin polymerisation: IC50=4.8 µM and anti-angiogenesis in Zebrafish: IC50=3.6 µM) based on tubulin and zebrafish assays, which displayed noteworthily nanomolar potency against a variety of leukaemia cell lines (IC50= 0.09-1.22 µM), especially K562 cells where apoptosis was induced. Molecular docking, molecular dynamics (MD) simulation, radioligand binding assay and cellular microtubule networks disruption results showed that 29e stably binds to the tubulin colchicine site. 29e significantly inhibited HUVEC tube formation, migration and invasion in vitro. Anti-angiogenesis in vivo was confirmed by zebrafish xenograft. 29e also prominently blocked K562 cell proliferation and metastasis in blood vessels and surrounding tissues of the zebrafish xenograft model. Together with promising physicochemical property and metabolic stability, 29e could be considered an effective anti-angiogenesis and -leukaemia drug candidate that binds to the tubulin colchicine site.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping