2. Academic Validation
  3. Development of Novel VEGFR2 Inhibitors Originating from Natural Product Analogues with Antiangiogenic Impact

Development of Novel VEGFR2 Inhibitors Originating from Natural Product Analogues with Antiangiogenic Impact

  • J Med Chem. 2021 Nov 11;64(21):15858-15867. doi: 10.1021/acs.jmedchem.1c01168.
Sung Min Cho 1,  Yonghyo Kim 1 2,  Yooju Jung 1,  Minjeong Ko 1,  Gyorgy Marko-Varga 1 2,  Ho Jeong Kwon 1 3
Affiliations

Affiliations

  • 1 Chemical Genomics Global Research Laboratory, Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
  • 2 Clinical Protein Science & Imaging, Biomedical Centre, Department of Biomedical Engineering, Lund University, BMC D13, 221 84 Lund, Sweden.
  • 3 Department of Internal Medicine, College of Medicine, Yonsei University, Seoul 03722, Republic of Korea.
PMID: 34730352 DOI: 10.1021/acs.jmedchem.1c01168
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/KDR/Flk-1) 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/KDR/Flk-1. Among these Voa structure analogues, Voa analogue 19 (V19) exhibited increased antiangiogenic potency against VEGF-induced VEGFR2/KDR/Flk-1 phosphorylation without cytotoxic effects. Moreover, treatment with V19 resulted in significant tumor cell death in a mouse xenograft model. In conclusion, this new VEGFR2/KDR/Flk-1 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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