Development of Novel VEGFR2 Inhibitors Originating from Natural Product Analogues with Antiangiogenic Impact
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| Title: | Development of Novel VEGFR2 Inhibitors Originating from Natural Product Analogues with Antiangiogenic Impact |
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| Authors: | Ho Jeong Kwon, György Marko-Varga, Sung Min Cho, Minjeong Ko, Yonghyo Kim, Yooju Jung |
| Contributors: | Sung Min Cho, Yonghyo Kim, Yooju Jung, Minjeong Ko, Gyorgy Marko-Varga, Ho Jeong Kwon |
| Source: | Journal of Medicinal Chemistry. 64:15858-15867 |
| Publisher Information: | American Chemical Society (ACS), 2021. |
| Publication Year: | 2021 |
| Subject Terms: | 0301 basic medicine, Biological Products / pharmacology, Nude, Antineoplastic Agents / pharmacology, Xenograft Model Antitumor Assaysz, Mice, Nude, Angiogenesis Inhibitors, Antineoplastic Agents, Biological Products / chemistry, Cell Line, Mice, Structure-Activity Relationship, 03 medical and health sciences, Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors, Drug Development, Cell Line, Tumor, Vascular Endothelial Growth Factor Receptor-2 / metabolism, Human Umbilical Vein Endothelial Cells, Animals, Humans, Phosphorylation, Biological Products, 0303 health sciences, Tumor, Cell Death, Angiogenesis Inhibitors / pharmacology, Vascular Endothelial Growth Factor Receptor-2, Xenograft Model Antitumor Assays, Angiogenesis Inhibitors / chemistry, Cell Death / drug effects |
| Description: | A novel natural small molecule, voacangine (Voa), has been discovered as a potent antiangiogenic compound. Notably, Voa directly binds the kinase domain of the vascular endothelial growth factor receptor 2 (VEGFR2) and thereby inhibits downstream signaling. Herein, we developed synthetic small molecules based on the unique chemical structure of Voa that directly and specifically target and modulate the kinase activity of VEGFR2. Among these Voa structure analogues, Voa analogue 19 (V19) exhibited increased antiangiogenic potency against VEGF-induced VEGFR2 phosphorylation without cytotoxic effects. Moreover, treatment with V19 resulted in significant tumor cell death in a mouse xenograft model. In conclusion, this new VEGFR2 modulator, inspired from the rigid scaffold of a natural compound, Voa, is presented as a potent candidate in the development of new antiangiogenic agents. |
| Document Type: | Article |
| Language: | English |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.1c01168 |
| Access URL: | https://pubmed.ncbi.nlm.nih.gov/34730352 https://europepmc.org/article/MED/34730352 https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.1c01168 |
| Rights: | STM Policy #29 CC BY NC ND |
| Accession Number: | edsair.doi.dedup.....1b748a59dbae2b2b37c2f803aa00f1cb |
| Database: | OpenAIRE |
Nájsť tento článok vo Web of Science | Abstract: | A novel natural small molecule, voacangine (Voa), has been discovered as a potent antiangiogenic compound. Notably, Voa directly binds the kinase domain of the vascular endothelial growth factor receptor 2 (VEGFR2) and thereby inhibits downstream signaling. Herein, we developed synthetic small molecules based on the unique chemical structure of Voa that directly and specifically target and modulate the kinase activity of VEGFR2. Among these Voa structure analogues, Voa analogue 19 (V19) exhibited increased antiangiogenic potency against VEGF-induced VEGFR2 phosphorylation without cytotoxic effects. Moreover, treatment with V19 resulted in significant tumor cell death in a mouse xenograft model. In conclusion, this new VEGFR2 modulator, inspired from the rigid scaffold of a natural compound, Voa, is presented as a potent candidate in the development of new antiangiogenic agents. |
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| ISSN: | 15204804 00222623 |
| DOI: | 10.1021/acs.jmedchem.1c01168 |