article · ACS Omega
Researchers designed and synthesised a series of tetrahydropyrimidine derivatives to serve as cytotoxic agents targeting both EGFR and VEGFR-2 enzymes. Laboratory evaluation across several cancer cell lines showed that derivatives 12 and 15 exhibited strong cytotoxic effects, achieving growth inhibition values close to the reference drug erlotinib. In enzyme assays, compounds 12, 14, and 15 effectively inhibited both target enzymes. Compound 15 emerged as the most potent candidate, displaying low nanomolar inhibitory concentrations against EGFR and especially VEGFR-2. Further laboratory assessments demonstrated that the newly developed molecules influence apoptotic pathways, indicating that programmed cell death contributes to their mechanism of action. Computational docking studies confirmed that the most active derivatives interact effectively with the active binding sites of both enzymes.
Dual targeting of cancer-related proteins such as EGFR and VEGFR-2 can improve treatment effectiveness and help overcome drug resistance. Identifying small molecules that concurrently block these pathways and induce programmed cell death offers useful starting points for oncology drug discovery, potentially leading to more potent therapies for cancer patients.
This work could enable the development of new small-molecule cancer therapeutics targeting EGFR and VEGFR-2 pathways. The primary potential users are pharmaceutical and biotechnology drug development teams seeking dual-kinase lead candidates. The research represents early-stage discovery, as it is limited to chemical synthesis, computational docking, and preliminary in vitro cellular and enzymatic assays without in vivo animal testing or clinical evaluation.
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We developed and synthesized tetrahydropyrimidine derivatives as possible cytotoxic agents to inhibit EGFR and VEGFR-2 in the present study. Our study completely assesses the cytotoxic efficiency of pyrimidine-based derivatives <b>4-15</b> against various cancer cell lines, revealing derivatives <b>12</b> and <b>15</b> for their remarkable activity with GI<sub>50</sub> values of 37 and 35 nM, respectively, when compared to the reference erlotinib (33 nM). In vitro enzyme assays showed that target compounds, particularly <b>12</b>, <b>14</b>, and <b>15</b>, effectively inhibited EGFR and VEGFR-2. <i>In vitro</i> enzyme testing revealed that compound <b>15</b> was the most promising, with IC<sub>50</sub> values of 84 and 3.50 nM for EGFR and VEGFR-2, respectively. Additionally, an <i>in vitro</i> assessment of the novel targets' apoptotic potential revealed that both pro-apoptotic and antiapoptotic behaviors were promising, indicating that the apoptotic induction pathway is a strongly proposed action method for the newly developed targets. Finally, molecular docking experiments are elaborately discussed to corroborate the exact binding interactions of the most active hybrids <b>12</b> and <b>15</b> with the EGFR and VEGFR-2 active sites.
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DOI: 10.1021/acsomega.4c01361
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