X-ray Crystal Structure-Guided Design and Optimization of 7H-Pyrrolo[2,3-d]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor,Journal of Medicinal Chemistry

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X-ray Crystal Structure-Guided Design and Optimization of 7H-Pyrrolo[2,3-d]pyrimidine-5-carbonitrile Scaffold as a Potent and Orally Active Monopolar Spindle 1 Inhibitor
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-05-04 , DOI: 10.1021/acs.jmedchem.1c00542
Younho Lee _{1,

2} , Hyunkyung Kim _{2,

3} , Haelee Kim ₄ , Ha Yeon Cho ₄ , Jun-Goo Jee ₃ , Kyung-Ah Seo ₂ , Jung Beom Son ₂ , Eunhwa Ko ₄ , Hwan Geun Choi ₄ , Nam Doo Kim ₂ , Ikyon Kim ₁

Affiliation

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：

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。

更新日期：2021-05-27

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