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
- Resource Type
- Article
- Authors
- Lee, Younho; Kim, Hyunkyung; Kim, Haelee; Cho, Ha Yeon; Jee, Jun-Goo; Seo, Kyung-Ah; Son, Jung Beom; Ko, Eunhwa; Choi, Hwan Geun; Kim, Nam Doo; Kim, Ikyon
- Source
- Journal of Medicinal Chemistry; May 2021, Vol. 64 Issue: 10 p6985-6995, 11p
- Subject
- Language
- ISSN
- 00222623; 15204804
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 vivoevaluation of candidate (9) is shown to effectively mitigate human TNBC cell proliferation.