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Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Monopolar spindle 1 (Mps1) kinase is crucial for activating the spindle assembly checkpoint (SAC), ensuring accurate chromosome segregation.
  • Dysregulation of SAC can lead to aneuploidy and cancer development.

Purpose of the Study:

  • To characterize novel Mps1 inhibitors, BAY 1161909 and BAY 1217389, for their potential in cancer therapy.
  • To evaluate the efficacy of these inhibitors as monotherapy and in combination with paclitaxel.

Main Methods:

  • In vitro kinase assays to determine Mps1 inhibition and selectivity.
  • Cellular assays to assess SAC activity, mitotic progression, and tumor cell proliferation.
  • In vivo studies using tumor xenograft models to evaluate therapeutic efficacy and toxicity.

Main Results:

  • BAY 1161909 and BAY 1217389 potently and selectively inhibited Mps1 kinase activity (IC50 < 10 nmol/L).
  • Inhibition of Mps1 abrogated SAC activity, induced mitotic breakthrough, and led to tumor cell death and inhibited proliferation.
  • Combination therapy with paclitaxel demonstrated significantly enhanced efficacy in xenograft models, including those resistant to paclitaxel, without increased toxicity.

Conclusions:

  • Novel Mps1 inhibitors BAY 1161909 and BAY 1217389 are effective in preclinical cancer models.
  • Abrogating the SAC via Mps1 inhibition represents a viable strategy to enhance the efficacy of antimitotic cancer drugs like paclitaxel and overcome treatment resistance.
  • Clinical studies are warranted to evaluate these Mps1 inhibitors in combination therapy.