Lu Dong, Yan Juan, Wang Lang, Liu Hongchun, Zeng Limin, Zhang Minmin, Duan Wenwen, Ji Yinchun, Cao Jingchen, Geng Meiyu, Shen Aijun, Hu Youhong
State Key Laboratory of Drug Research, Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
ACS Med Chem Lett. 2017 Jul 18;8(8):830-834. doi: 10.1021/acsmedchemlett.7b00172. eCollection 2017 Aug 10.
Simultaneous blockade of more than one pathway is considered to be a promising approach to overcome the low efficacy and acquired resistance of cancer therapies. Thus, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound, , inhibited c-Met kinase and HDAC1, with IC values of 0.71 and 38 nM, respectively, and showed efficient antiproliferative activities against both EBC-1 and HCT-116 cells with greater potency than the reference drug Chidamide. Western blot analysis revealed that compound inhibited phosphorylation of c-Met and c-Met downstream signaling proteins and increased expression of Ac-H3 and p21 in EBC-1 cells in a dose-dependent manner. Our study presents novel compounds for the further exploration of dual c-Met/HDAC pathway inhibition achieved with a single molecule.
同时阻断多条信号通路被认为是克服癌症治疗低疗效和获得性耐药的一种有前景的方法。因此，通过融合c-Met和HDAC抑制剂的药效基团，设计并合成了一系列新型的c-Met/HDAC双功能抑制剂。最具活性的化合物， ，抑制c-Met激酶和HDAC1，IC值分别为0.71和38 nM，并对EBC-1和HCT-116细胞均显示出高效的抗增殖活性，其效力高于参考药物西达本胺。蛋白质免疫印迹分析表明，该化合物以剂量依赖性方式抑制EBC-1细胞中c-Met及其下游信号蛋白的磷酸化，并增加Ac-H3和p21的表达。我们的研究提出了新型化合物，用于进一步探索通过单分子实现双c-Met/HDAC信号通路抑制。
