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

Sung Min Cho; Yonghyo Kim; Yooju Jung; Minjeong Ko; Gyorgy Marko-Varga; Ho Jeong Kwon

doi:10.1021/acs.jmedchem.1c01168

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

Sung Min Cho, Yonghyo Kim, Yooju Jung, Minjeong Ko, Gyorgy Marko-Varga, Ho Jeong Kwon

Research output: Contribution to journal › Article › peer-review

2 Citations (Scopus)

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.

Original language	English
Pages (from-to)	15858-15867
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	64
Issue number	21
DOIs	https://doi.org/10.1021/acs.jmedchem.1c01168
Publication status	Published - 2021 Nov 11

Bibliographical note

Funding Information:
The authors thank Dr. Yong-Beom Lim for his critical comments on this study. This work was partially supported by grants from the National Research Foundation of Korea (MSIP; 2015K1A1A2028365, 2015M3A9C4076321, 2018M3A9C4076477, 2021R1A3B1077371) and the Brain Korea 21 Plus Project and ICONS (Institute of Convergence Science), Yonsei University. Faculty of Medicine, Lund University, Lund, Sweden (IKVL, V2017/1818), The Anders and Birgit Andersson Research Foundation, Lund, Sweden (RFh20I9-022), and Berta Kamprad Foundation, Lund, Sweden (FBKS-2020-18).

Funding Information:
The authors thank Dr. Yong-Beom Lim for his critical comments on this study. This work was partially supported by grants from the National Research Foundation of Korea (MSIP; 2015K1A1A2028365, 2015M3A9C4076321 2018M3A9C4076477, 2021R1A3B1077371) and the Brain Korea 21 Plus Project and ICONS (Institute of Convergence Science), Yonsei University. Faculty of Medicine, Lund University, Lund, Sweden (IKVL, V2017/1818), The Anders and Birgit Andersson Research Foundation, Lund, Sweden (RFh20I9-022) and Berta Kamprad Foundation, Lund, Sweden (FBKS-2020-18).

Publisher Copyright:
© 2021 American Chemical Society.

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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10.1021/acs.jmedchem.1c01168

Cite this

@article{558d748c029f4fa0881ec793d223910f,

title = "Development of Novel VEGFR2 Inhibitors Originating from Natural Product Analogues with Antiangiogenic Impact",

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.",

author = "Cho, {Sung Min} and Yonghyo Kim and Yooju Jung and Minjeong Ko and Gyorgy Marko-Varga and Kwon, {Ho Jeong}",

note = "Funding Information: The authors thank Dr. Yong-Beom Lim for his critical comments on this study. This work was partially supported by grants from the National Research Foundation of Korea (MSIP; 2015K1A1A2028365, 2015M3A9C4076321, 2018M3A9C4076477, 2021R1A3B1077371) and the Brain Korea 21 Plus Project and ICONS (Institute of Convergence Science), Yonsei University. Faculty of Medicine, Lund University, Lund, Sweden (IKVL, V2017/1818), The Anders and Birgit Andersson Research Foundation, Lund, Sweden (RFh20I9-022), and Berta Kamprad Foundation, Lund, Sweden (FBKS-2020-18). Funding Information: The authors thank Dr. Yong-Beom Lim for his critical comments on this study. This work was partially supported by grants from the National Research Foundation of Korea (MSIP; 2015K1A1A2028365, 2015M3A9C4076321 2018M3A9C4076477, 2021R1A3B1077371) and the Brain Korea 21 Plus Project and ICONS (Institute of Convergence Science), Yonsei University. Faculty of Medicine, Lund University, Lund, Sweden (IKVL, V2017/1818), The Anders and Birgit Andersson Research Foundation, Lund, Sweden (RFh20I9-022) and Berta Kamprad Foundation, Lund, Sweden (FBKS-2020-18). Publisher Copyright: {\textcopyright} 2021 American Chemical Society.",

year = "2021",

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doi = "10.1021/acs.jmedchem.1c01168",

language = "English",

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AU - Cho, Sung Min

AU - Kim, Yonghyo

AU - Jung, Yooju

AU - Ko, Minjeong

AU - Marko-Varga, Gyorgy

AU - Kwon, Ho Jeong

N1 - Funding Information: The authors thank Dr. Yong-Beom Lim for his critical comments on this study. This work was partially supported by grants from the National Research Foundation of Korea (MSIP; 2015K1A1A2028365, 2015M3A9C4076321, 2018M3A9C4076477, 2021R1A3B1077371) and the Brain Korea 21 Plus Project and ICONS (Institute of Convergence Science), Yonsei University. Faculty of Medicine, Lund University, Lund, Sweden (IKVL, V2017/1818), The Anders and Birgit Andersson Research Foundation, Lund, Sweden (RFh20I9-022), and Berta Kamprad Foundation, Lund, Sweden (FBKS-2020-18). Funding Information: The authors thank Dr. Yong-Beom Lim for his critical comments on this study. This work was partially supported by grants from the National Research Foundation of Korea (MSIP; 2015K1A1A2028365, 2015M3A9C4076321 2018M3A9C4076477, 2021R1A3B1077371) and the Brain Korea 21 Plus Project and ICONS (Institute of Convergence Science), Yonsei University. Faculty of Medicine, Lund University, Lund, Sweden (IKVL, V2017/1818), The Anders and Birgit Andersson Research Foundation, Lund, Sweden (RFh20I9-022) and Berta Kamprad Foundation, Lund, Sweden (FBKS-2020-18). Publisher Copyright: © 2021 American Chemical Society.

PY - 2021/11/11

Y1 - 2021/11/11

N2 - 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.

AB - 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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ER -

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

Abstract

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