Discovery and identification of new non-ATP competitive FGFR1 inhibitors with therapeutic potential on non-small-cell lung cancer
Discovery and identification of new non-ATP competitive FGFR1 inhibitors with therapeutic potential on non-small-cell lung cancer
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发现和鉴定具有非小细胞肺癌治疗潜力的新型非 ATP 竞争性 FGFR1 抑制剂
DOI：
10.1016/j.canlet.2013.10.016
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发表时间：
2014-03-01
期刊：
影响因子：
9.7
通讯作者：
Liang, Guang
中科院分区：
文献类型：
--
作者：
Wang, Yi;Cai, Yuepiao;Liang, Guang
成纤维细胞生长因子受体（FGFR）酪氨酸激酶已被认为是癌症治疗的靶标，并且通过小分子抑制FGF/FGFR信号传导作为癌症的治疗方法具有很大的兴趣。通常，抑制剂模拟ATP结构并阻断ATP和FGFR激酶之间的结合。在这里，两个新的，非ATP竞争性，选择性，不可逆的FGFR 1抑制剂，A114和A117，通过激酶抑制试验从156个合成的双芳基-1，4-二烯-3-酮衍生物中鉴定。通过分子对接，预测了FGFR 1的“DFG-OUT”非活性构象结合模式。A114和A117通过靶向FGFR 1在体外和体内均显示出显著的抗肿瘤活性。(C)2013爱思唯尔爱尔兰有限公司版权所有。
Fibroblast growth factor receptor (FGFR) tyrosine kinases have been regarded as a target for cancer treatment, and there is much interest in inhibiting FGF/FGFR signaling by small molecules as a therapeutic approach to cancer. Generally, inhibitors mimics ATP structure and block the binding between ATP and FGFR kinase. Here, two novel, non-ATP-competitive, selective, irreversible FGFR1 inhibitors, A114 and A117, were identified via kinase inhibitory assay from 156 synthetic bisaryl-1,4-dien-3-one derivatives. A "DFG-OUT" inactive conformation binding mode with FGFR1 was predicted by molecular docking. A114 and A117 showed significant anti-tumor activity both in vitro and in vivo via targeting FGFR1. (C) 2013 Elsevier Ireland Ltd. All rights reserved.