化学
生物利用度
IC50型
药理学
药代动力学
酪氨酸激酶
激酶
体内
生长抑制
酪氨酸激酶抑制剂
紫杉醇
苏氨酸
生物化学
细胞生长
磷酸化
癌症
癌症研究
体外
内科学
信号转导
医学
丝氨酸
生物
生物技术
作者
Ming Huang,Yongjun Huang,Jing Guo,Lei Yu,Yu Chen,Xiaolu Wang,Jinfeng Luo,Yanhui Huang,Zhengchao Tu,Xiaoyun Lu,Yong Xu,Zhimin Zhang,Zhang Zhang,Ke Ding
标识
DOI:10.1016/j.ejmech.2020.113023
摘要
A series of pyrido [2, 3-d]pyrimidin-7(8H)-ones were designed and synthesized as new selective orally bioavailable Threonine Tyrosine Kinase (TTK) inhibitors. One of the representative compounds, 5o, exhibited strong binding affinity with a Kd value of 0.15 nM, but was significantly less potent against a panel of 402 wild-type kinases at 100 nM. The compound also potently inhibited the kinase activity of TTK with an IC50 value of 23 nM, induced chromosome missegregation and aneuploidy, and suppressed proliferation of a panel of human cancer cell lines with low μM IC50 values. Compound 5o demonstrated good oral pharmacokinetic properties with a bioavailability value of 45.3% when administered at a dose of 25 mg/kg in rats. Moreover, a combination therapy of 5o with paclitaxel displayed promising in vivo efficacy against the HCT-116 human colon cancer xenograft model in nude mice with a Tumor Growth Inhibition (TGI) value of 78%. Inhibitor 5o may provide a new research tool for further validating therapeutic potential of TTK inhibition.
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