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.

中文翻译：

---

发现和开发有效、选择性和口服生物可利用的 CHK1 候选抑制剂：5-((4-((3-Amino-3-methylbutyl)amino)-5-(trifluoromethyl)pyrimidin-2-yl)amino)picolinonitrile

检查点激酶 1 (CHK1) 在 DNA 损伤反应通路中发挥重要作用，是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 CHK1 抑制剂，以克服先导化合物1的局限性，该化合物只能静脉给药。经过详细调查，我们确定化合物6c是一种口服 CHK1 抑制剂，这表明在小鼠中的血浆暴露量要高得多。化合物6c也表现出良好的激酶选择性。此外，它单独对 MV-4-11 细胞具有显着的抗增殖作用，与吉西他滨联合对 HT-29、A549 和 RPMI-8226 细胞具有协同作用。此外，化合物6c可以抑制 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作用。因此，发现化合物6c是一种选择性和口服潜在的抗癌 CHK1 抑制剂。