Wu Jianzhang, Ji Jiansong, Weng Bixia, Qiu Peihong, Kanchana Karvannan, Wei Tao, Wang Yi, Cai Yuepiao, Li Xiaokun, Liang Guang
Chemical Biology Research Center, School of Pharmaceutical Sciences, WenzhouMedical Universtiy, Wenzhou zhejiang China. These Authors contributed equally to this work.
Department of Interventional Radiology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China. These Authors contributed equally to this work.
Oncotarget. 2014 Jun 30;5(12):4543-53. doi: 10.18632/oncotarget.2122.
Accumulating evidence suggests that high expression of FGFR1 is closely related to the development of lung cancer especially in non-small cell lung cancers (NSCLC), to which non-ATP competitive inhibitors represent an effective therapeutical approach due to their good specificity. Herein, a series of NDGA analogues with the framework of bisaryl-1,4-dien-3-one as novel FGFR1 inhibitors have been designed and screened. Among them Aea4 and Aea25 showed strong FGFR1`inhibition and high selectivity over other receptor kinases. The kinase inhibitory assay in different ATP concentrations and computer-assistant molecular docking showed that the FGFR1 inhibition mode of both Aea4 and Aea25 was non-ATP-competitive. The in vitro and in vivo study on anticancer efficacy of Aea4 and Aea25 against non-small cell lung cancer involves inhibition of cell proliferation, apoptosis induction and cell cycle arrest with no toxicity. Thus, these two novel non-ATP competitive inhibitors derived from NDGA may have a great therapeutic potential in the treatment of NSCLC. This work also provides a structural lead for the design of new non-ATP-competitive FGFR1 inhibitors.
越来越多的证据表明，FGFR1的高表达与肺癌尤其是非小细胞肺癌（NSCLC）的发生密切相关，对于非小细胞肺癌，非ATP竞争性抑制剂因其良好的特异性而代表了一种有效的治疗方法。在此，设计并筛选了一系列具有双芳基-1,4-二烯-3-酮骨架的NDGA类似物作为新型FGFR1抑制剂。其中，Aea4和Aea25对FGFR1表现出强烈的抑制作用，并且对其他受体激酶具有高选择性。在不同ATP浓度下的激酶抑制试验和计算机辅助分子对接表明，Aea4和Aea25对FGFR1的抑制模式均为非ATP竞争性。对Aea4和Aea25抗非小细胞肺癌的抗癌疗效进行的体外和体内研究涉及抑制细胞增殖、诱导凋亡和细胞周期阻滞，且无毒性。因此，这两种源自NDGA的新型非ATP竞争性抑制剂在NSCLC治疗中可能具有巨大的治疗潜力。这项工作也为设计新的非ATP竞争性FGFR1抑制剂提供了结构先导。
