Triple-negative breast cancer (TNBC) is an aggressive breast-cancer subtype associated with poor prognosis and high relapse rates. Monopolar spindle 1 kinase (MPS1) is an apical dual-specificity protein kinase that is over-expressed in TNBC. We herein report a highly selective MPS1 inhibitor based on a 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile scaffold. Our lead optimization was guided by key X-ray crystal structure analysis. In vivo evaluation of candidate (9) is shown to effectively mitigate human TNBC cell proliferation.

中文翻译：

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X射线晶体结构指导的7 H-吡咯并[2,3 - d ]嘧啶-5-腈骨架作为有效的口服活性单极纺锤体1抑制剂的设计与优化

三阴性乳腺癌（TNBC）是一种侵袭性乳腺癌亚型，与不良预后和高复发率相关。单极纺锤体1激酶（MPS1）是一种顶端双特异性蛋白激酶，在TNBC中过表达。我们在此报告了一种基于7 H-吡咯并[2,3 - d ]嘧啶-5-腈骨架的高选择性MPS1抑制剂。我们的铅优化是通过关键的X射线晶体结构分析进行的。候选物的体内评估（9）显示可有效缓解人TNBC细胞增殖。