Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors
Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors
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DOI：
10.1016/j.ejmech.2021.113648
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发表时间：
2021-06-24
影响因子：
6.7
通讯作者：
Li, Jianqi
中科院分区：
文献类型：
--
作者：
Huang, Daowei;Yang, Jixia;Li, Jianqi
HGF/Met信号通路在许多类型的癌症中过度表达，并与肿瘤的发生和转移密切相关。因此，我们开发了新的n-苯基嘧啶-2胺衍生物，测试了它们对c-Met激酶的抑制活性，大多数化合物（15a-i, 15o-r， 20和34a-c）可以抑制靶标，IC50值在550.8 nM至15.0 nM之间。随后，化合物15b、15d、15f、15i、15o、15r、20、34a和34b对c-Met敏感的肿瘤细胞系（PC-3、Panc-1、HepG2、HCT116和Caki-1）也表现出较高的抗增殖活性，IC50值在0.53 ~ 1.37 μ m之间，先导化合物34a表现出较强的c-Met抑制活性（IC50: 15.0 nM）和抗增殖活性。此外，34a在小鼠体内也表现出良好的药代动力学特性（F%: 59.3），并且在临床前研究中具有可接受的安全性。进一步的对接研究表明，34a在atp结合位点与c-Met有共同的相互作用，这表明34a可能是c-Met抑制剂的潜在候选者。(C) 2021 Elsevier Masson SAS。版权所有。
The HGF/Met signaling pathway is over-expressed in many types of cancers and closely related to oncogenesis and metastasis. Thus, we developed novel N-phenylpyrimidin-2-amine derivatives to test their inhibitory activities towards c-Met kinase, and most of the compounds (15a-i, 15o-r, 20 and 34a-c) could inhibit the target with IC50 values from 550.8 nM to 15.0 nM. Subsequently, compound 15b, 15d, 15f, 15i, 15o, 15r, 20, 34a and 34b also showed high antiproliferative activities in c-Met sensitive tumor cell lines (PC-3, Panc-1, HepG2, HCT116 and Caki-1) with IC50 values from 0.53 to 1.37 mu M. The lead compound 34a displayed outstanding c-Met inhibitory activity ( IC50: 15.0 nM) and antiproliferative activities. Furthermore, 34a also performed favorable pharmacokinetic properties in mice (F%: 59.3) and an acceptable safety profile in preclinical studies. Further docking studies showed a common interaction of 34a with c-Met at the ATP-binding site, which indicated that 34a could be a potential candidate for c-Met inhibitors. (C) 2021 Elsevier Masson SAS. All rights reserved.