Zeng Jing, Deng Qichuan, Chen Zheng, Yan Shuang, Dong Qin, Zhang Yuyu, Cui Yuan, Li Ling, He Yuxin, Shi Jianyou
School of Food and Bioengineering, Xihua University, Chengdu, Sichuan 610039, China.
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Science & Sichuan Provincial People's Hospital, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610072, China.
Bioorg Chem. 2024 May;146:107278. doi: 10.1016/j.bioorg.2024.107278. Epub 2024 Mar 9.
VEGFR, a receptor tyrosine kinase inhibitor (TKI), is an important regulatory factor that promotes angiogenesis and vascular permeability. It plays a significant role in processes such as tumor angiogenesis, tumor cell invasion, and metastasis. VEGFR is mainly composed of three subtypes: VEGFR-1, VEGFR-2, and VEGFR-3. Among them, VEGFR-2 is the crucial signaling receptor for VEGF, which is involved in various pathological and physiological functions. At present, VEGFR-2 is closely related to a variety of cancers, such as non-small cell lung cancer (NSCLC), Hepatocellular carcinoma, Renal cell carcinoma, breast cancer, gastric cancer, glioma, etc. Consequently, VEGFR-2 serves as a crucial target for various cancer treatments. An increasing number of VEGFR inhibitors have been discovered to treat cancer, and they have achieved tremendous success in the clinic. Nevertheless, VEGFR inhibitors often exhibit severe cytotoxicity, resistance, and limitations in indications, which weaken the clinical therapeutic effect. In recent years, many small molecule inhibitors targeting VEGFR have been identified with anti-drug resistance, lower cytotoxicity, and better affinity. Here, we provide an overview of the structure and physiological functions of VEGFR, as well as some VEGFR inhibitors currently in clinical use. Also, we summarize the in vivo and in vitro activities, selectivity, structure-activity relationship, and therapeutic or preventive use of VEGFR small molecule inhibitors reported in patents in the past three years (2021-2023), thereby presenting the prospects and insights for the future development of targeted VEGFR inhibitors.
血管内皮生长因子受体（VEGFR）是一种受体酪氨酸激酶抑制剂（TKI），是促进血管生成和血管通透性的重要调节因子。它在肿瘤血管生成、肿瘤细胞侵袭和转移等过程中发挥着重要作用。VEGFR主要由三种亚型组成：VEGFR-1、VEGFR-2和VEGFR-3。其中，VEGFR-2是VEGF的关键信号受体，参与多种病理和生理功能。目前，VEGFR-2与多种癌症密切相关，如非小细胞肺癌（NSCLC）、肝细胞癌、肾细胞癌、乳腺癌、胃癌、神经胶质瘤等。因此，VEGFR-2是各种癌症治疗的关键靶点。越来越多的VEGFR抑制剂被发现可用于治疗癌症，并且它们在临床上取得了巨大成功。然而，VEGFR抑制剂常常表现出严重的细胞毒性、耐药性以及适应症方面的局限性，这削弱了临床治疗效果。近年来，许多靶向VEGFR的小分子抑制剂被鉴定出来，它们具有抗耐药性、较低的细胞毒性和更好的亲和力。在此，我们概述了VEGFR的结构和生理功能，以及一些目前正在临床使用的VEGFR抑制剂。此外，我们总结了过去三年（2021 - 2023年）专利中报道的VEGFR小分子抑制剂的体内和体外活性、选择性、构效关系以及治疗或预防用途，从而展现靶向VEGFR抑制剂未来发展的前景和见解。
