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Design, synthesis, and anti-hepatocellular carcinoma activity evaluation of aryl Lenvatinib derivatives: Exploring
Lian Sun1, Yao Xiao1, Qiang Li1
1Sichuan Engineering Research Center for Biomimetic Synthesis of Natural Drugs, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu 610031, China.
Abstract:
Lenvatinib, a first-line multi-kinase inhibitor targeting VEGFR-2 tyrosine kinase, demonstrates significant therapeutic potential in hepatocellular carcinoma (HCC) treatment. Guided by structure-based rational design targeting, the critical binding domains of VEGFR-2 and lenvatinib, a novel series of aryl-substituted lenvatinib derivatives were synthesized via palladium-catalyzed Suzuki cross-coupling reactions. Systematic evaluation revealed superior anti-proliferative effects of these derivatives against HepG2 and Hep3B human HCC cell lines compared to the parent compound. Particularly, the 3-isopropyl aryl derivative 3i exhibited threefold enhanced potency (IC50 = 2.4 ± 0.28 μM) over lenvatinib. Mechanistic investigations demonstrated that compound 3i significantly promoted HCC cell apoptosis through caspase-dependent pathways. The IC50 values of compounds 3i against VEGFR-2 kinases (IC50 = 22.2 ± 0.52 nM) is showed activity comparable to that of lenvatinib (IC50 = 16.4 ± 1.90 nM). Molecular docking and 100 ns molecular dynamics simulations further elucidated that the 3i achieved enhanced binding affinity through optimized hydrophobic contacts within the ATP-binding pocket of VEGFR-2. This structure-activity relationship study provides valuable insights for developing next-generation VEGFR-2 inhibitors, with compound 3i emerging as a promising drug candidate warranting further preclinical evaluation.
Insights
Researchers developed new lenvatinib derivatives targeting VEGFR-2 for hepatocellular carcinoma (HCC). A novel derivative, compound 3i, showed enhanced anti-proliferative effects and promoted apoptosis in HCC cells, indicating its potential as a drug candidate.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Lenvatinib is a multi-kinase inhibitor targeting VEGFR-2, showing therapeutic promise for hepatocellular carcinoma (HCC).
- Structure-based drug design can optimize kinase inhibitor efficacy and specificity.
Purpose of the Study:
- To synthesize and evaluate novel aryl-substituted lenvatinib derivatives.
- To investigate the anti-proliferative and apoptotic effects of these derivatives on HCC cell lines.
- To elucidate the molecular mechanisms underlying their enhanced activity against VEGFR-2.
Main Methods:
- Synthesis of lenvatinib derivatives using palladium-catalyzed Suzuki cross-coupling reactions.
- In vitro anti-proliferative assays using HepG2 and Hep3B human HCC cell lines.
- Apoptosis induction studies via caspase-dependent pathways.
- Enzyme inhibition assays and molecular dynamics simulations to assess VEGFR-2 binding affinity.
Main Results:
- Novel aryl-substituted lenvatinib derivatives demonstrated superior anti-proliferative activity compared to lenvatinib.
- Compound 3i, a 3-isopropyl aryl derivative, exhibited significantly enhanced potency (IC50 = 2.4 ± 0.28 μM) and promoted HCC cell apoptosis.
- Compound 3i showed comparable inhibitory activity against VEGFR-2 kinases (IC50 = 22.2 ± 0.52 nM) as lenvatinib (IC50 = 16.4 ± 1.90 nM).
- Molecular docking and simulations revealed that compound 3i achieves enhanced binding affinity through optimized hydrophobic interactions in the VEGFR-2 ATP-binding pocket.
Conclusions:
- The synthesized lenvatinib derivatives, particularly compound 3i, represent promising next-generation VEGFR-2 inhibitors for HCC treatment.
- Structure-activity relationship studies provide a foundation for developing optimized inhibitors with improved efficacy.
- Compound 3i warrants further preclinical investigation as a potential therapeutic agent for hepatocellular carcinoma.
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