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Development of the First Covalent Monopolar Spindle Kinase 1 (MPS1/TTK) Inhibitor

Ricardo A M Serafim1,2,3, André da Silva Santiago2,3, Martin P Schwalm4,5

  • 1Department of Pharmaceutical/Medicinal Chemistry, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076 Tübingen, Germany.

Journal of Medicinal Chemistry
|February 15, 2022
PubMed

Insights

Researchers developed RMS-07, the first irreversible covalent inhibitor targeting Monopolar spindle kinase 1 (MPS1/TTK). This novel drug shows potent activity against aggressive cancers, offering new therapeutic strategies.

Area of Science:

  • Molecular Biology
  • Medicinal Chemistry
  • Cancer Therapeutics

Background:

  • Monopolar spindle kinase 1 (MPS1/TTK) is crucial for the mitotic checkpoint.
  • MPS1/TTK is a validated therapeutic target for aggressive cancers, including triple-negative breast cancer.
  • Irreversible inhibitors with long drug-target residence times are hypothesized to enhance MPS1 inhibition efficacy.

Purpose of the Study:

  • To design and characterize the first irreversible covalent inhibitor of MPS1/TTK.
  • To investigate the potential of targeting a specific cysteine residue in the MPS1/TTK hinge region.
  • To evaluate the compound's potency, selectivity, and anti-cancer activity.

Main Methods:

  • Structure-based drug design and chemical synthesis of RMS-07.
  • Biochemical assays to determine MPS1/TTK inhibitory activity and kinase selectivity.
  • Cellular assays to assess target engagement and anti-proliferative effects in cancer cell lines.
  • Mass spectrometry and X-ray crystallography to confirm covalent binding mode.

Main Results:

  • RMS-07 identified as the first irreversible covalent MPS1/TTK inhibitor.
  • RMS-07 demonstrates potent MPS1 inhibition and high selectivity against kinases with a similar cysteine residue and a broader panel.
  • Significant cellular target engagement and pronounced anti-cancer activity observed across various cancer cell lines.
  • Covalent binding confirmed through mass spectrometry and structural analysis.

Conclusions:

  • The development of RMS-07 establishes the covalent ligandability of MPS1/TTK.
  • This proof-of-concept opens new avenues for designing targeted MPS1 inhibitors.
  • Potential for novel chemical probes and therapeutics for aggressive cancers targeting MPS1/TTK.

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