School of Pharmacy, Lanzhou University, Lanzhou 730000, China.
Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, Medical College of China Three Gorges University, Yichang 443003, China.
Bioorg Chem. 2023 Apr;133:106425. doi: 10.1016/j.bioorg.2023.106425. Epub 2023 Feb 15.
Vascular epidermal growth factor receptor-2 (VEGFR-2), as an important tyrosine transmembrane protein, plays an important role in regulating endothelial cell proliferation and migration, regulating angiogenesis and other biological functions. VEGFR-2 is aberrantly expressed in many malignant tumors, and it is also related to the occurrence, development, and growth of tumors and drug resistance. Currently, there are nine VEGFR-2 targeted inhibitors approved by US.FDA for clinical use as anticancer drugs. Due to the limited clinical efficacy and potential toxicity of VEGFR inhibitors, it is necessary to develop new strategies to improve the clinical efficacy of VEGFR inhibitors. The development of multitarget therapy, especially dual-target therapy, has become a hot research field of cancer therapy, which may provide an effective strategy with higher therapeutic efficacy, pharmacokinetic advantages and low toxicity. Many groups have reported that the therapeutic effects could be improved by simultaneously inhibiting VEGFR-2 and other targets, such as EGFR, c-Met, BRAF, HDAC, etc. Therefore, VEGFR-2 inhibitors with multi-targeting capabilities have been considered to be promising and effective anticancer agents for cancer therapy. In this work, we reviewed the structure and biological functions of VEGFR-2, and summarized the drug discovery strategies, and inhibitory activities of VEGFR-2 inhibitors with multi-targeting capabilities reported in recent years. This work might provide the reference for the development of VEGFR-2 inhibitors with multi-targeting capabilities as novel anticancer agents.
血管内皮生长因子受体-2（VEGFR-2）作为一种重要的酪氨酸跨膜蛋白，在调节内皮细胞增殖和迁移、调节血管生成等生物学功能方面发挥着重要作用。VEGFR-2 在许多恶性肿瘤中异常表达，与肿瘤的发生、发展和生长以及耐药性有关。目前，美国 FDA 批准了 9 种 VEGFR-2 靶向抑制剂作为抗癌药物在临床上使用。由于 VEGFR 抑制剂的临床疗效有限和潜在毒性，有必要开发新的策略来提高 VEGFR 抑制剂的临床疗效。多靶点治疗的发展，特别是双靶点治疗，已成为癌症治疗的热门研究领域，这可能为提高治疗效果、药代动力学优势和降低毒性提供了一种有效的策略。许多研究小组报告称，同时抑制 VEGFR-2 和其他靶点，如 EGFR、c-Met、BRAF、HDAC 等，可以提高治疗效果。因此，具有多靶点作用的 VEGFR-2 抑制剂被认为是治疗癌症的有前途和有效的抗癌药物。在这项工作中，我们综述了 VEGFR-2 的结构和生物学功能，并总结了近年来具有多靶点作用的 VEGFR-2 抑制剂的药物发现策略和抑制活性。这项工作可能为开发具有多靶点作用的 VEGFR-2 抑制剂作为新型抗癌药物提供参考。
