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 K_d 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.

一系列吡啶并[2，3- d ]嘧啶-7（8 ħ） -酮，设计并作为新的选择性口服生物可利用苏氨酸酪氨酸激酶（TTK）抑制剂合成。代表性化合物之一5o表现出很强的结合亲和力，K _d值为0.15 nM，但在100 nM时对一组402种野生型激酶的效力明显较低。该化合物还有效地抑制TTK的激酶活性，其IC ₅₀ 23纳米的值，诱发染色体错误分离和非整倍，并用低μMIC人癌细胞系的面板的抑制增殖₅₀值。化合物5o在大鼠中以25 mg / kg的剂量给药时，具有良好的口服药代动力学特性，生物利用度值为45.3％。此外，5o与紫杉醇的联合治疗在裸鼠中显示出对HCT-116人结肠癌异种移植模型的有希望的体内疗效，其肿瘤生长抑制（TGI）值为78％。抑制剂5o可能为进一步验证TTK抑制的治疗潜力提供一种新的研究工具。