Computational and experimental studies were applied to the discovery of a series of novel vascular endothelial growth factor receptor 2 (VEGFR-2) inhibitors. Eight compounds exhibited nanomolar IC₅₀ values against VEGFR-2, and compounds 6, 19, 22, and 23 showed potent antiproliferative effects against several cell lines. Particularly, compound 23 behaved better than FDA approved drugs, sorafenib and sunitinib, in antiproliferative activity against cell lines related to all nine tumor types tested (GI₅₀ values), and it was better or comparable in safety (LC₅₀ values). Compound 23 even demonstrated a high potency on one of the drug-resistant cell lines (NCI/ADR-RES) responsible for ovarian cancer and cell lines contributing to prostate cancer, regarded as one of the VEGF/VEGFR pathway drug-resistant tumors. This compound is likely a promising candidate for the treatment of leukemia, non-small cell lung cancer (NSCLC), colon cancer, ovarian cancer, and breast cancer with a suitable balance of both efficacy and safety.

中文翻译：

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新型强效VEGFR-2抑制剂对癌细胞系具有显着的抗增殖活性的发现

计算和实验研究被应用于发现一系列新型血管内皮生长因子受体2（VEGFR-2）抑制剂。八种化合物显示出纳摩尔IC _50个值针对VEGFR-2，和化合物6，19，22，和23显示出对数种细胞系有效的抗增殖作用。特别是，化合物23在针对与所有9种测试肿瘤类型相关的细胞系的抗增殖活性（GI ₅₀值）方面均优于FDA批准的药物索拉非尼和舒尼替尼，并且在安全性方面更好或相当（LC ₅₀值）。化合物23甚至在负责卵巢癌的一种耐药细胞系（NCI / ADR-RES）和导致前列腺癌的细胞系中被证明是一种高效药，该细胞系被认为是VEGF / VEGFR途径耐药性肿瘤之一。这种化合物可能是治疗白血病，非小细胞肺癌（NSCLC），结肠癌，卵巢癌和乳腺癌的有前途的候选者，并且在功效和安全性之间达到适当的平衡。