Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor
Discovery of a potent and selective covalent threonine tyrosine kinase (TTK) inhibitor
复制标题
DOI：
10.1016/j.bioorg.2023.107053
复制
发表时间：
2023-12-29
影响因子：
5.1
通讯作者：
Xu，Shilin
中科院分区：
文献类型：
--
作者：
Sun，Yaoliang;Chen，Zhiwen;Xu，Shilin
苏氨酸酪氨酸激酶（TTK）是纺锤体组装检查点的重要组成部分，在有丝分裂中起关键作用。TTK已被确定为人类癌症的潜在治疗靶点。在这里，我们描述了我们的设计，合成和评价一类共价TTK抑制剂，以16（SYL1073）为例。化合物16有效抑制TTK激酶，ic50为0.016 μM，在一组激酶中显示出更高的选择性。质谱分析表明，16共价结合在TTK激酶结构域铰链区域的C604半胱氨酸残基上。此外，16在抑制各种人类癌细胞系的生长方面具有很强的效力，优于其相对可逆的抑制剂，并引发强大的下游效应。综上所述，化合物16为进一步优化人类癌症治疗药物的开发提供了有价值的先导化合物。
Threonine tyrosine kinase (TTK) is a critical component of the spindle assembly checkpoint and plays a pivotal role in mitosis. TTK has been identified as a potential therapeutic target for human cancers. Here, we describe our design, synthesis and evaluation of a class of covalent TTK inhibitors, exemplified by16(SYL1073). Compound16potently inhibits TTK kinase with an IC50of 0.016 μM and displays improved selectivity in a panel of kinases. Mass spectrometry analysis reveals that16covalently binds to the C604 cysteine residue in the hinge region of the TTK kinase domain. Furthermore,16achieves strong potency in inhibiting the growth of various human cancer cell lines, outperforming its relative reversible inhibitor, and eliciting robust downstream effects. Taken together, compound16provides a valuable lead compound for further optimization toward the development of drug for treatment of human cancers.