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.
Younho LeeHyunkyung KimHaelee KimHa Yeon ChoJun-Goo JeeKyung-Ah SeoJung Beom SonEunhwa KoHwan Geun ChoiNam Doo KimIkyon KimPublished in: Journal of medicinal chemistry (2021)
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.
Keyphrases
- crystal structure
- poor prognosis
- protein kinase
- long non coding rna
- cell proliferation
- high resolution
- dual energy
- endothelial cells
- tissue engineering
- cell cycle
- computed tomography
- electron microscopy
- magnetic resonance imaging
- pluripotent stem cells
- free survival
- magnetic resonance
- signaling pathway
- structural basis