Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile
Discovery and Development of a Potent, Selective, and Orally Bioavailable CHK1 Inhibitor Candidate: 5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile
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发现和开发一种有效的、选择性的、口服生物可利用的 CHK1 抑制剂候选物：5-((4-((3-氨基-3-甲基丁基)氨基)-5-(三氟甲基)嘧啶-2-基)氨基)吡啶甲腈
DOI：
10.1021/acs.jmedchem.1c00994
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发表时间：
2021-10-19
影响因子：
7.3
通讯作者：
Liu, Tao
中科院分区：
文献类型：
--
作者：
Jin, Tingting;Xu, Lei;Liu, Tao
检查点激酶1（Checkpoint kinase 1，CHK 1）在DNA损伤反应途径中起重要作用，是一个潜在的抗癌药物靶点。在这项研究中，我们使用三氟甲基取代的策略来获得口服生物可利用的CHK 1抑制剂，以克服先导化合物1的局限性，其只能静脉内给药。经过详细研究，我们将化合物6c鉴定为口服CHK 1抑制剂，其在小鼠中表现出相当高的血浆暴露。化合物6c也显示出良好的激酶选择性。此外，它在MV-4-11细胞中单独表现出显著的抗增殖作用，并且与吉西他滨组合在HT-29、A549和RPMI-8226细胞中表现出协同作用。此外，化合物6c可抑制MV-4-11异种移植小鼠模型中的肿瘤生长。6c和吉西他滨的组合在HT-29异种移植小鼠模型中表现出协同效应。因此，发现化合物6c是选择性和口服潜在的抗癌CHK 1抑制剂。
Checkpoint kinase 1 (CHK1) plays an important role in the DNA damage response pathway, being a potential anti-cancer drug target. In this study, we used a strategy for trifluoromethyl substitution to obtain orally bioavailable CHK1 inhibitors to overcome the limitations of lead compound 1, which can only be administered intravenously. After detailed investigation, we identified compound 6c as an oral CHK1 inhibitor, which demonstrated a considerably higher plasma exposure in mice. Compound 6c also showed good kinase selectivity. Moreover, it exhibited a significant antiproliferative effect in MV-4-11 cells singly and a synergistic effect in combination with gemcitabine in HT-29, A549, and RPMI-8226 cells. Additionally, compound 6c could inhibit tumor growth in the MV-4-11 xenograft mouse model. The combination of 6c and gemcitabine exhibited synergistic effect in the HT-29 xenograft mouse model. Thus, compound 6c was found to be a selective and oral potential anticancer CHK1 inhibitor.