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

  • J Med Chem. 2021 May 27;64(10):6985-6995. 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
Affiliations
  • 1. College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, South Korea.
  • 2. Voronoibio, S11 Floor, 32 Songdogwahak-ro, Yeonsu-gu, Incheon 21984, South Korea.
  • 3. Research Institute of Pharmaceutical Researches, College of Pharmacy, Kyungpook National University, Daegu 41566, Republic of Korea.
  • 4. B2Sbio, S23 Floor, 32 Songdogwahak-ro, Yeonsu-gu, Incheon 21984, South Korea.
PMID: 33942608 DOI: 10.1021/acs.jmedchem.1c00542
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.

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