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

Younho Lee, Hyunkyung Kim, Haelee Kim, Ha Yeon Cho, Jun Goo Jee, Kyung Ah Seo, Jung Beom Son, Eunhwa Ko, Hwan Geun Choi, Nam Doo Kim, Ikyon Kim

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)6985-6995
Number of pages11
JournalJournal of Medicinal Chemistry
Volume64
Issue number10
DOIs
Publication statusPublished - 2021 May 27

Bibliographical note

Funding Information:
We thank the National Research Foundation of Korea (NRF-2018R1A6A1A03023718 and NRF-2020R1A2C2005961 to I.K.) for generous financial support.

Publisher Copyright:
© 2021 American Chemical Society.

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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