关键词： HCC anticancer inhibitors molecular modeling ureido of 4-phenylthiazole derivatives

Mesh ： Humans Receptor, IGF Type 1 / antagonists & inhibitors metabolism Cell Proliferation / drug effects Hep G2 Cells Thiazoles / chemistry pharmacology Protein Kinase Inhibitors / pharmacology chemistry chemical synthesis Antineoplastic Agents / pharmacology chemistry chemical synthesis Apoptosis / drug effects Liver Neoplasms / drug therapy pathology metabolism Carcinoma, Hepatocellular / drug therapy pathology metabolism Cell Movement / drug effects Structure-Activity Relationship Molecular Docking Simulation Receptors, Somatomedin / antagonists & inhibitors metabolism Molecular Structure Cell Line, Tumor Sorafenib / pharmacology chemistry Models, Molecular

来  源：   DOI：10.3390/molecules29112653   PDF(Pubmed)

Abstract：
The existing kinase inhibitors for hepatocellular carcinoma (HCC) have conferred survival benefits but are hampered by adverse effects and drug resistance, necessitating the development of novel agents targeting distinct pathways. To discover potent new anti-HCC compounds, we leveraged scaffold hopping from Sorafenib and introduced morpholine/piperidine moieties to develop ureido-substituted 4-phenylthiazole analogs with optimized physicochemical properties and binding interactions. Notably, compound 27 exhibited potent cytotoxicity against HepG2 cells (IC50 = 0.62 ± 0.34 μM), significantly exceeding Sorafenib (IC50 = 1.62 ± 0.27 μM). Mechanistic investigations revealed that compound 27 potently inhibited HCC cell migration and colony formation, and it induced G2/M arrest and early-stage apoptosis. Kinase profiling revealed IGF1R as a key target, which compound 27 potently inhibited (76.84% at 10 μM). Molecular modeling substantiated compound 27\'s strong binding to IGF1R via multiple hydrogen bonds. Computational predictions indicate favorable drug-like properties for compound 27. These findings provide a promising drug candidate for the treatment of HCC patients.
摘要：
现有的用于肝细胞癌（HCC）的激酶抑制剂已赋予生存益处，但受到不良反应和耐药性的阻碍。有必要开发靶向不同途径的新型药物。为了发现有效的新的抗HCC化合物，我们利用索拉非尼的支架跳变,并引入吗啉/哌啶部分,开发了具有优化物理化学性质和结合相互作用的脲基取代的4-苯基噻唑类似物.值得注意的是,化合物27对HepG2细胞表现出有效的细胞毒性（IC50=0.62±0.34μM），显著超过索拉非尼(IC50=1.62±0.27μM)。机制研究表明，化合物27有效抑制HCC细胞迁移和集落形成，并诱导G2/M期阻滞和早期凋亡。激酶分析显示IGF1R是关键靶标，该化合物27有效抑制(10μM时76.84%)。分子模拟证实了化合物27通过多个氢键与IGF1R的强结合。计算预测表明化合物27具有有利的药物样性质。这些发现为HCC患者的治疗提供了有希望的候选药物。
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