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Discovery of A Novel Series of Quinazoline-Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents.

ABSTRACT: Considering the pivotal role of angiogenesis in solid tumor progression, we developed a novel series of quinazoline-thiazole hybrids (SA01-SA07) as antiproliferative and anti-angiogenic agents. Four out of the seven compounds displayed superior antiproliferative activity (IC₅₀ =1.83-4.24 µM) on HepG2 cells compared to sorafenib (IC₅₀ = 6.28 µM). The affinity towards the VEGFR2 kinase domain was assessed through in silico prediction by molecular docking, molecular dynamics studies, and MM-PBSA. The series displayed a high degree of similarity to sorafenib regarding the binding pose within the active site of VEGFR2, with a different orientation of the 4-substituted-thiazole moieties in the allosteric pocket. Molecular dynamics and MM-PBSA evaluations identified SA05 as the hybrid forming the most stable complex with VEGFR2 compared to sorafenib. The impact of the compounds on vascular cell proliferation was assessed on EA.hy926 cells. Six compounds (SA01-SA05, SA07) displayed superior anti-proliferative activity (IC₅₀ = 0.79-5.85 µM) compared to sorafenib (IC₅₀ = 6.62 µM). The toxicity was evaluated on BJ cells. Further studies of the anti-angiogenic effect of the most promising compounds, SA04 and SA05, through the assessment of impact on EA.hy296 motility using a wound healing assay and in ovo potential in a CAM assay compared to sorafenib, led to the confirmation of the anti-angiogenic potential.

SUBMITTER: Sandor A

PROVIDER: S-EPMC10886515 | biostudies-literature | 2024 Feb

REPOSITORIES: biostudies-literature

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Discovery of A Novel Series of Quinazoline-Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents.

Șandor Alexandru A Fizeșan Ionel I Ionuț Ioana I Marc Gabriel G Moldovan Cristina C Oniga Ilioara I Pîrnău Adrian A Vlase Laurian L Petru Andreea-Elena AE Macasoi Ioana I Oniga Ovidiu O

Biomolecules 20240212 2

Considering the pivotal role of angiogenesis in solid tumor progression, we developed a novel series of quinazoline-thiazole hybrids (SA01-SA07) as antiproliferative and anti-angiogenic agents. Four out of the seven compounds displayed superior antiproliferative activity (IC50 =1.83-4.24 µM) on HepG2 cells compared to sorafenib (IC50 = 6.28 µM). The affinity towards the VEGFR2 kinase domain was assessed through in silico prediction by molecular docking, molecu ...[more]

PMID: 38397456

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Project description:BackgroundAnti-angiogenic therapy in certain cancers has been associated with improved control of tumor growth and metastasis. Development of anti-angiogenic agents has, however, been saddled with higher attrition rate due to suboptimal efficacy, narrow therapeutic windows, or development of organ-specific toxicities. The aim of this study was to evaluate the translational ability of the zebrafish efficacy-toxicity model to stratify anti-angiogenic agents based on efficacy, therapeutic windows, and off-target effects to streamline the compound selection process in anti-angiogenic discovery.MethodsThe embryonic model of zebrafish was employed for studying angiogenesis and toxicity. The zebrafish were treated with anti-angiogenic compounds to evaluate their effects on angiogenesis and zebrafish-toxicity parameters. Angiogenesis was measured by scoring the development of subintestinal vessels. Toxicity was evaluated by calculating the median lethal concentration, the lowest observed effect concentration, and gross morphological changes. Results of efficacy and toxicity were used to predict the therapeutic window.ResultsIn alignment with the clinical outcomes, the zebrafish assays demonstrated that vascular endothelial growth factor receptor (VEGFR) inhibitors are the most potent anti-angiogenic agents, followed by multikinase inhibitors and inhibitors of endothelial cell proliferation. The toxicity assays reported cardiac phenotype in zebrafish treated with VEGFR inhibitors and multikinase inhibitors with VEGFR activity suggestive of cardiotoxic potential of these compounds. Several other pathological features were reported for multikinase inhibitors suggestive of off-target effects. The predicted therapeutic window was translational with the clinical trial outcomes of the anti-angiogenic agents. The zebrafish efficacy-toxicity approach could stratify anti-angiogenic agents based on the mechanism of action and delineate chemical structure-driven biological activity of anti-angiogenic compounds.ConclusionThe zebrafish efficacy-toxicity approach can be used as a predictive model for translational anti-angiogenic drug discovery to streamline compound selection, resulting in safer and efficacious anti-angiogenic agents entering the clinics.

Dataset Information

Discovery of A Novel Series of Quinazoline-Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents.

Publications

Discovery of A Novel Series of Quinazoline-Thiazole Hybrids as Potential Antiproliferative and Anti-Angiogenic Agents.

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