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Ref Type Journal Article
PMID (26832791)
Authors Wengner AM, Siemeister G, Koppitz M, Schulze V, Kosemund D, Klar U, Stoeckigt D, Neuhaus R, Lienau P, Bader B, Prechtl S, Raschke M, Frisk AL, von Ahsen O, Michels M, Kreft B, von Nussbaum F, Brands M, Mumberg D, Ziegelbauer K
Title Novel Mps1 Kinase Inhibitors with Potent Antitumor Activity.
Journal Molecular cancer therapeutics
Vol 15
Issue 4
Date 2016 Apr
URL
Abstract Text Monopolar spindle 1 (Mps1) has been shown to function as the key kinase that activates the spindle assembly checkpoint (SAC) to secure proper distribution of chromosomes to daughter cells. Here, we report the structure and functional characterization of two novel selective Mps1 inhibitors, BAY 1161909 and BAY 1217389, derived from structurally distinct chemical classes. BAY 1161909 and BAY 1217389 inhibited Mps1 kinase activity with IC50 values below 10 nmol/L while showing an excellent selectivity profile. In cellular mechanistic assays, both Mps1 inhibitors abrogated nocodazole-induced SAC activity and induced premature exit from mitosis ("mitotic breakthrough"), resulting in multinuclearity and tumor cell death. Both compounds efficiently inhibited tumor cell proliferation in vitro (IC50 nmol/L range). In vivo, BAY 1161909 and BAY 1217389 achieved moderate efficacy in monotherapy in tumor xenograft studies. However, in line with its unique mode of action, when combined with paclitaxel, low doses of Mps1 inhibitor reduced paclitaxel-induced mitotic arrest by the weakening of SAC activity. As a result, combination therapy strongly improved efficacy over paclitaxel or Mps1 inhibitor monotreatment at the respective MTDs in a broad range of xenograft models, including those showing acquired or intrinsic paclitaxel resistance. Both Mps1 inhibitors showed good tolerability without adding toxicity to paclitaxel monotherapy. These preclinical findings validate the innovative concept of SAC abrogation for cancer therapy and justify clinical proof-of-concept studies evaluating the Mps1 inhibitors BAY 1161909 and BAY 1217389 in combination with antimitotic cancer drugs to enhance their efficacy and potentially overcome resistance. Mol Cancer Ther; 15(4); 583-92. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
BAY1217389 BAY1217389 6 0
Drug Name Trade Name Synonyms Drug Classes Drug Description
BAY1217389 BAY 1217389 MPS1 Inhibitor 25 BAY1217389, an inhibitor of TTK (MPS1), inhibits the spindle assembly checkpoint to induce cell death (PMID: 26832791).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown triple-receptor negative breast cancer not applicable BAY1217389 + Paclitaxel Preclinical Actionable In a preclinical study, BAY1217389, in combination with Taxol (paclitaxel), had increased efficacy in inhibiting tumor growth in xenograft models of triple-negative breast cancer, compared to Taxol (paclitaxel) alone (PMID: 26832791). detail... 26832791
Unknown unknown Advanced Solid Tumor not applicable BAY1161909 Preclinical Actionable In a preclinical study, BAY1161909 inhibited proliferation of a variety of human solid tumor cell lines in culture (PMID: 26832791). detail... 26832791
Unknown unknown Advanced Solid Tumor not applicable BAY1217389 Preclinical Actionable In a preclinical study, BAY1217389 inhibited proliferation of a variety of human solid tumor cell lines in culture (PMID: 26832791). detail... 26832791
Unknown unknown lung non-small cell carcinoma not applicable BAY1217389 + Paclitaxel Preclinical Actionable In a preclinical study, the combination of BAY1217389 and Taxol (paclitaxel) resulted in enhanced growth inhibition compared to Taxol (paclitaxel) alone in non-small cell lung cancer xenograft models (PMID: 26832791). 26832791
Unknown unknown ovarian cancer not applicable BAY1161909 Preclinical Actionable In a preclinical study, BAY1161909 demonstrated moderate efficacy in ovarian cancer xenograft models (PMID: 26832791). 26832791
Unknown unknown lung non-small cell carcinoma not applicable BAY1161909 + Paclitaxel Preclinical Actionable In a preclinical study, the combination of BAY1161909 and Taxol (paclitaxel) resulted in enhanced growth inhibition compared to Taxol (paclitaxel) alone in non-small cell lung cancer xenograft models (PMID: 26832791). 26832791
Unknown unknown ovarian cancer not applicable BAY1217389 Preclinical Actionable In a preclinical study, BAY1217389 demonstrated moderate efficacy in ovarian cancer xenograft models (PMID: 26832791). 26832791
Unknown unknown triple-receptor negative breast cancer not applicable BAY1161909 + Paclitaxel Preclinical Actionable In a preclinical study, BAY1161909, in combination with Taxol (paclitaxel), had increased efficacy in xenograft models of triple-negative breast cancer compared to Taxol (paclitaxel) alone, resulting in complete tumor regression (PMID: 26832791). 26832791