X-ray Crystal Structure-Guided Design and Optimization of 7H-Pyrrolo[2,3-d]pyrimidine-5-carbonitrile Scaffold as a
Younho Lee1,2, Hyunkyung Kim2,3, Haelee Kim4
1College of Pharmacy and Yonsei Institute of Pharmaceutical Sciences, Yonsei University, 85 Songdogwahak-ro, Yeonsu-gu, Incheon 21983, South Korea.
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.
Insights
Researchers developed a selective inhibitor targeting Monopolar spindle 1 kinase (MPS1), an enzyme overexpressed in triple-negative breast cancer (TNBC). This new compound effectively reduced TNBC cell proliferation in vivo.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with poor prognosis and high recurrence rates.
- Monopolar spindle 1 kinase (MPS1) is a protein kinase frequently overexpressed in TNBC, making it a potential therapeutic target.
Purpose of the Study:
- To design and synthesize a highly selective inhibitor of MPS1.
- To optimize the inhibitor scaffold for potential therapeutic application against TNBC.
Main Methods:
- Utilized a 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile scaffold for inhibitor design.
- Employed X-ray crystallography to guide lead optimization of MPS1 inhibitors.
- Conducted in vivo evaluations of the lead candidate (compound 9) in TNBC models.
Main Results:
- A highly selective MPS1 inhibitor was successfully developed.
- Lead optimization, informed by structural analysis, yielded a potent candidate.
- Compound 9 demonstrated significant mitigation of human TNBC cell proliferation in vivo.
Conclusions:
- The novel 7H-pyrrolo[2,3-d]pyrimidine-5-carbonitrile-based MPS1 inhibitor shows promise for TNBC treatment.
- Structural insights were crucial for developing a selective and effective MPS1 inhibitor.
- Further investigation of this compound is warranted for its therapeutic potential in TNBC.
