Key Laboratory of Regenerative Biology and Institute of Chemical Biology, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, #190 Kaiyuan Road, Guangzhou Science Park, Guangzhou, Guangdong Province 510530, China.
Invest New Drugs. 2012 Apr;30(2):490-507. doi: 10.1007/s10637-010-9577-1. Epub 2010 Nov 16.
Receptor tyrosine kinases (RTKs) modulate a variety of cellular events, including cell proliferation, differentiation, mobility and apoptosis. In addition, RTKs have been validated as targets for cancer therapies. Microtubules are another class of proven targets for many clinical anticancer drugs. Here, we report that 1-(4-chloro-3-(trifluoromethyl) phenyl)-3-(2-cyano-4-hydroxyphenyl)urea (D181) functions as both a receptor tyrosine kinase inhibitor and a tubulin polymerization enhancer. D181 displayed potent inhibitory activities against a panel of RTKs, including Flt3, VEGFR, cKit, FGFR1 and PDGFRβ. D181 also enhanced tubulin polymerization and modified the secondary structure of tubulin proteins to disrupt their dynamic instability. Because of synergistic cooperation, D181 strongly inhibited the proliferation of various cancer cell lines, induced LoVo cell cycle arrest in the G1 and M phases and suppressed tumor growth in nude mice bearing human LoVo and HT29 xenografts. Our studies have provided a new, promising lead compound and novel clues for multi-target anticancer drug design and development.
受体酪氨酸激酶 (RTKs) 调节多种细胞事件，包括细胞增殖、分化、迁移和凋亡。此外，RTKs 已被证实为癌症治疗的靶点。微管是许多临床抗癌药物的另一种已证实的靶标。在这里，我们报告 1-(4-氯-3-(三氟甲基)苯基)-3-(2-氰基-4-羟基苯基)脲 (D181) 既作为受体酪氨酸激酶抑制剂，又作为微管聚合增强剂。D181 对一系列 RTKs 表现出强大的抑制活性，包括 Flt3、VEGFR、cKit、FGFR1 和 PDGFRβ。D181 还增强了微管聚合，并修饰了微管蛋白的二级结构，破坏其动态不稳定性。由于协同合作，D181 强烈抑制了各种癌细胞系的增殖，诱导 LoVo 细胞周期停滞在 G1 和 M 期，并抑制了携带人 LoVo 和 HT29 异种移植物的裸鼠肿瘤生长。我们的研究为多靶点抗癌药物设计和开发提供了一种新的、有前途的先导化合物和新线索。
