Isatin-triazole/imidazole hybrids as dual CDK2/VEGFR2 inhibitors with potent anti-cancer activity: design, synthesis,
Zainab M Elsayed1, Marwa Balaha2, Haytham O Tawfik3
1Scientific Research and Innovation Support Unit, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.
Abstract:
Cyclin-dependent kinase 2 (CDK2) and vascular endothelial growth factor receptor 2 (VEGFR2) are essential for the development of tumor angiogenesis and the cell cycle, respectively. Inhibiting both kinases at the same time has therefore become a sensible anticancer tactic. A number of unique hybrid compounds containing isatin-triazole and isatin-imidazole scaffolds were created and thoroughly described in an effort to find dual CDK2/VEGFR2 inhibitors. Compounds 5d, 5k, and 10 showed the strongest antiproliferative activity against breast (MCF7) and prostate (PC3) cancer cell lines among the produced derivatives. Notably, compound 10 showed the most inhibitory potency, with IC50 values of 0.058 μM for VEGFR2 and 0.789 μM for CDK2, respectively. These values are on par with or higher than those of the reference standards, roscovitine and sunitinib. Additionally, a biological study showed that compounds 5d and 5 k had negligible off-target toxicity and were selectively lethal to cancer cells compared to normal HaCaT keratinocytes. Furthermore, cell cycle studies revealed that compound 5d produced S-phase arrest, whereas compounds 5 k and 10 mostly caused G-phase arrest, in line with their kinase inhibition profiles. Additionally, the potent analogues 5d and 10 substantially decreased colony formation and tumoral cell migration. Molecular docking and dynamics simulations helped to clarify the possible binding interactions inside the ATP-binding sites of CDK2 and VEGFR2, confirming the dual-binding mechanism that underlies their potent effects. According to all of these findings, compound 10 is a potential dual CDK2/VEGFR2 inhibitor that offers a helpful foundation for the development and optimization of future multitarget anticancer agents.
Insights
New hybrid compounds targeting both cyclin-dependent kinase 2 (CDK2) and vascular endothelial growth factor receptor 2 (VEGFR2) show potent anticancer activity. Compound 10 demonstrates significant inhibition of tumor growth and migration, offering a promising lead for multitarget cancer therapy.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- Cyclin-dependent kinase 2 (CDK2) regulates the cell cycle, while vascular endothelial growth factor receptor 2 (VEGFR2) is crucial for tumor angiogenesis.
- Simultaneous inhibition of CDK2 and VEGFR2 presents a viable strategy for anticancer drug development.
- Isatin-triazole and isatin-imidazole scaffolds were explored for their potential as dual inhibitors.
Purpose of the Study:
- To synthesize and characterize novel hybrid compounds as dual inhibitors of CDK2 and VEGFR2.
- To evaluate the antiproliferative activity of these compounds against breast and prostate cancer cell lines.
- To investigate the mechanism of action, including cell cycle effects and molecular interactions.
Main Methods:
- Synthesis of isatin-triazole and isatin-imidazole hybrid compounds.
- In vitro antiproliferative assays against MCF7 and PC3 cancer cell lines.
- Enzyme inhibition assays for CDK2 and VEGFR2.
- Cell cycle analysis and assessment of colony formation and migration.
- Molecular docking and dynamics simulations.
Main Results:
- Compounds 5d, 5k, and 10 exhibited significant antiproliferative effects.
- Compound 10 displayed potent inhibition of VEGFR2 (IC50 = 0.058 μM) and CDK2 (IC50 = 0.789 μM), comparable to reference drugs.
- Compounds 5d and 5k showed selective toxicity towards cancer cells over normal cells and induced S-phase and G-phase arrest, respectively.
- Compounds 5d and 10 reduced colony formation and tumor cell migration.
- Molecular simulations confirmed dual-binding interactions within the ATP-binding sites of CDK2 and VEGFR2.
Conclusions:
- Compound 10 is identified as a potent dual CDK2/VEGFR2 inhibitor with significant anticancer potential.
- The synthesized compounds provide a valuable foundation for developing novel multitarget anticancer agents.
- The study highlights the efficacy of targeting both cell cycle and angiogenesis pathways simultaneously.
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