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Identification and ...
Identification and validation of VEGFR2 kinase as a target of voacangine by a systematic combination of DARTS and MSI
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- Kim, Yonghyo (author)
- Lund University,Lunds universitet,Avdelningen för Biomedicinsk teknik,Institutionen för biomedicinsk teknik,Institutioner vid LTH,Lunds Tekniska Högskola,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Clinical Protein Science and Imaging,Forskargrupper vid Lunds universitet,Department of Biomedical Engineering,Departments at LTH,Faculty of Engineering, LTH,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups,Yonsei University
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- Sugihara, Yutaka (author)
- Lund University,Lunds universitet,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Clinical Protein Science and Imaging,Forskargrupper vid Lunds universitet,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups
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- Kim, Tae Young (author)
- Yonsei University
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- Cho, Sung Min (author)
- Yonsei University
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- Kim, Jin Young (author)
- Korea Basic Science Institute
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- Lee, Ju Yeon (author)
- Korea Basic Science Institute
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- Yoo, Jong Shin (author)
- Korea Basic Science Institute
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- Song, Doona (author)
- Yonsei University
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- Han, Gyoonhee (author)
- Yonsei University
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- Rezeli, Melinda (author)
- Lund University,Lunds universitet,Avdelningen för Biomedicinsk teknik,Institutionen för biomedicinsk teknik,Institutioner vid LTH,Lunds Tekniska Högskola,Clinical Protein Science and Imaging,Forskargrupper vid Lunds universitet,Department of Biomedical Engineering,Departments at LTH,Faculty of Engineering, LTH,Lund University Research Groups
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- Welinder, Charlotte (author)
- Lund University,Lunds universitet,Avdelningen för Biomedicinsk teknik,Institutionen för biomedicinsk teknik,Institutioner vid LTH,Lunds Tekniska Högskola,Tumörmikromiljö,Sektion I,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Clinical Protein Science and Imaging,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Department of Biomedical Engineering,Departments at LTH,Faculty of Engineering, LTH,Tumor microenvironment,Section I,Department of Clinical Sciences, Lund,Faculty of Medicine,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
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- Appelqvist, Roger (author)
- Lund University,Lunds universitet,Avdelningen för Biomedicinsk teknik,Institutionen för biomedicinsk teknik,Institutioner vid LTH,Lunds Tekniska Högskola,Clinical Protein Science and Imaging,Forskargrupper vid Lunds universitet,Department of Biomedical Engineering,Departments at LTH,Faculty of Engineering, LTH,Lund University Research Groups
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- Marko-Varga, György (author)
- Lund University,Lunds universitet,Avdelningen för Biomedicinsk teknik,Institutionen för biomedicinsk teknik,Institutioner vid LTH,Lunds Tekniska Högskola,Clinical Protein Science and Imaging,Forskargrupper vid Lunds universitet,Department of Biomedical Engineering,Departments at LTH,Faculty of Engineering, LTH,Lund University Research Groups,Tokyo Medical University,Yonsei University
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- Kwon, Ho Jeong (author)
- Yonsei University
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(creator_code:org_t)
- 2020-03-27
- 2020
- English.
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In: Biomolecules. - : MDPI AG. - 2218-273X. ; 10:4
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Abstract
Subject headings
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- Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Keyword
- Anti-angiogenesis
- Curcumin
- Label-free method for drugs
- Mechanism of action
- Natural products
- Receptor tyrosine kinases
- Target identification
- Target validation
Publication and Content Type
- art (subject category)
- ref (subject category)
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To the university's database
- By the author/editor
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Kim, Yonghyo
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Sugihara, Yutaka
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Kim, Tae Young
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Cho, Sung Min
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Kim, Jin Young
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Lee, Ju Yeon
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show more...
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Yoo, Jong Shin
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Song, Doona
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Han, Gyoonhee
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Rezeli, Melinda
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Welinder, Charlo ...
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Appelqvist, Roge ...
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Marko-Varga, Gyö ...
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Kwon, Ho Jeong
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Medical Biotechn ...
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and Medical Biotechn ...
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Biomolecules
- By the university
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Lund University