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Exploration of acridine scaffold as a potentially interesting scaffold for discovering novel multi-target VEGFR-2 and
Xudong Luan1, Chunmei Gao, Nannan Zhang
1The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
Abstract:
VEGFR-2 and Src kinases both play important roles in cancers. In certain cancers, Src works synergistically with VEGFR-2 to promote its activation. Development of multi-target drugs against VEGFR-2 and Src is of therapeutic advantage against these cancers. By using molecular docking and SVM virtual screening methods and based on subsequent synthesis and bioassay studies, we identified 9-aminoacridine derivatives with an acridine scaffold as potentially interesting novel dual VEGFR-2 and Src inhibitors. The acridine scaffold has been historically used for deriving topoisomerase inhibitors, but has not been found in existing VEGFR-2 inhibitors and Src inhibitors. A series of 21 acridine derivatives were synthesized and evaluated for their antiproliferative activities against K562, HepG-2, and MCF-7 cells. Some of these compounds showed better activities against K562 cells in vitro than imatinib. The structure-activity relationships (SAR) of these compounds were analyzed. One of the compounds (7r) showed low μM activity against K562 and HepG-2 cancer cell-lines, and inhibited VEGFR-2 and Src at inhibition rates of 44% and 8% at 50μM, respectively, without inhibition of topoisomerase. Moreover, 10μM compound 7r could reduce the levels of activated ERK1/2 in a time dependant manner, a downstream effector of both VEGFR-2 and Src. Our study suggested that acridine scaffold is a potentially interesting scaffold for developing novel multi-target kinase inhibitors such as VEGFR-2 and Src dual inhibitors.
Insights
Novel acridine derivatives show promise as dual inhibitors of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) and Src kinases, crucial targets in cancer therapy. These compounds exhibit potent anti-cancer activity, offering a new therapeutic strategy against various malignancies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) and Src kinases are critical in cancer progression.
- Synergistic activation of VEGFR-2 and Src drives certain cancer types.
- Multi-targeting inhibitors offer therapeutic advantages against these cancers.
Purpose of the Study:
- To identify novel dual inhibitors targeting both VEGFR-2 and Src kinases.
- To explore the potential of the acridine scaffold for developing multi-kinase inhibitors.
- To evaluate the antiproliferative and inhibitory activities of synthesized acridine derivatives.
Main Methods:
- Molecular docking and Support Vector Machine (SVM) virtual screening were employed for initial identification.
- A series of 21 acridine derivatives were synthesized.
- Antiproliferative assays against K562, HepG-2, and MCF-7 cancer cell lines were performed.
- Inhibition assays for VEGFR-2, Src, and topoisomerase were conducted.
- Structure-activity relationships (SAR) were analyzed.
- Western blotting was used to assess the impact on downstream signaling pathways (ERK1/2).
Main Results:
- 9-aminoacridine derivatives with an acridine scaffold were identified as potential dual VEGFR-2 and Src inhibitors.
- Some synthesized compounds demonstrated superior in vitro antiproliferative activity against K562 cells compared to imatinib.
- Compound 7r exhibited low μM activity against K562 and HepG-2 cells.
- Compound 7r inhibited VEGFR-2 (44%) and Src (8%) at 50μM without affecting topoisomerase.
- Compound 7r reduced activated ERK1/2 levels in a time-dependent manner at 10μM.
Conclusions:
- The acridine scaffold is a promising platform for developing novel multi-target kinase inhibitors.
- Acridine derivatives can be designed to effectively inhibit both VEGFR-2 and Src.
- Compound 7r represents a lead candidate for further development as a dual VEGFR-2 and Src inhibitor in cancer therapy.