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Development of MPS1 Inhibitors: Recent Advances and Perspectives
Yangjie Zeng1, Xiaodong Ren1, Pengyao Jin1
1Medical College, Guizhou University, Guiyang, Guizhou 550025, China.
Abstract:
Monopolar spindle kinase 1 (MPS1) plays a pivotal role as a dual-specificity kinase governing spindle assembly checkpoint activation and sister chromatid separation in mitosis. Its overexpression has been observed in various human malignancies. MPS1 reduces spindle assembly checkpoint sensitivity, allowing tumor cells with a high degree of aneuploidy to complete mitosis and survive. Thus, MPS1 has emerged as a promising candidate for cancer therapy. Despite the identification of numerous MPS1 inhibitors, only five have advanced to clinical trials with none securing FDA approval for cancer treatment. In this perspective, we provide a concise overview of the structural and functional characteristics of MPS1 by highlighting its relevance to cancer. Additionally, we explore the structure-activity relationships, selectivity, and pharmacokinetics of MPS1 inhibitors featuring diverse scaffolds. Moreover, we review the reported work on enhancing MPS1 inhibitor selectivity, offering valuable insights into the discovery of novel, highly potent small-molecule MPS1 inhibitors.
Insights
Monopolar spindle kinase 1 (MPS1) is crucial for cell division and often overexpressed in cancers. Inhibiting MPS1 shows promise for cancer therapy, but developing effective drugs remains challenging.
Area of Science:
- Cell Biology
- Molecular Oncology
- Drug Discovery
Background:
- Monopolar spindle kinase 1 (MPS1) is a dual-specificity kinase essential for mitosis, regulating spindle assembly checkpoint (SAC) activation and sister chromatid separation.
- MPS1 overexpression is linked to aneuploidy and survival in various human cancers, making it a significant therapeutic target.
- Despite its therapeutic potential, challenges remain in developing clinically approved MPS1 inhibitors.
Purpose of the Study:
- To provide an overview of MPS1's structure, function, and role in cancer.
- To explore structure-activity relationships, selectivity, and pharmacokinetics of diverse MPS1 inhibitors.
- To review strategies for enhancing MPS1 inhibitor selectivity for improved cancer treatment.
Main Methods:
- Literature review of MPS1's role in cancer.
- Analysis of structure-activity relationships for various MPS1 inhibitor scaffolds.
- Examination of pharmacokinetic properties and selectivity enhancement strategies for MPS1 inhibitors.
Main Results:
- MPS1's overexpression contributes to tumor cell survival by reducing SAC sensitivity.
- Numerous MPS1 inhibitors with diverse scaffolds have been identified, but clinical translation is limited.
- Strategies to improve inhibitor selectivity are crucial for developing potent small-molecule drugs.
Conclusions:
- MPS1 is a validated cancer target due to its role in mitosis and aneuploidy.
- Further research into MPS1 inhibitor selectivity and pharmacokinetics is essential for clinical success.
- Developing novel, highly potent small-molecule MPS1 inhibitors holds promise for future cancer therapies.
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