Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer

Mason, Jacqueline M.; Wei, Xin; Fletcher, Graham C.; Kiarash, Reza; Brokx, Richard D.; Hodgson, Richard; Beletskaya, Irina; Bray, Mark R.; Mak, Tak W.

doi:10.1073/pnas.1700234114

Cited by 103 publications

(147 citation statements)

References 34 publications

(48 reference statements)

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“…Recently, several potent MPS1 inhibitors have been developed 26,34–36 and two of them, BAY1161909 and BAY1217389, are currently in phase I clinical trials 27,37 . Our data provide a rationale for the future clinical evaluation of combined therapies utilizing TTFields and MPS1 inhibitors in patients with GBM.…”

Section: Discussionmentioning

confidence: 99%

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

et al. 2018

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Tumor treating fields (TTFields) are approved for glioblastoma (GBM) therapy. TTFields disrupt cell division by inhibiting spindle fiber formation. Spindle assembly checkpoint (SAC) inhibition combined with antimitotic drugs synergistically decreases glioma cell growth in cell culture and mice. We hypothesized that SAC inhibition will increase TTFields efficacy. Human GBM cells (U-87 MG, GaMG) were treated with TTFields (200 kHz, 1.7 V/cm) and/or the SAC inhibitor MPS1-IN-3 (IN-3, 4 µM). Cells were counted after 24, 48, and 72 h of treatment and at 24 and 72 h after end of treatment (EOT). Flow cytometry, immunofluorescence microscopy, Annexin-V staining and TUNEL assay were used to detect alterations in cell cycle and apoptosis after 72 h of treatment. The TTFields/IN-3 combination decreased cell proliferation after 72 h compared to either treatment alone (−78.6% vs. TTFields, P = 0.0337; −52.6% vs. IN-3, P = 0.0205), and reduced the number of viable cells (62% less than seeded). There was a significant cell cycle shift from G1 to G2/M phase (P < 0.0001). The apoptotic rate increased to 44% (TTFields 14%, P = 0.0002; IN-3 4%, P < 0.0001). Cell growth recovered 24 h after EOT with TTFields and IN-3 alone, but the combination led to further decrease by 92% at 72 h EOT if IN-3 treatment was continued (P = 0.0288). The combination of TTFields and SAC inhibition led to earlier and prolonged effects that significantly augmented the efficacy of TTFields and highlights a potential new targeted multimodal treatment for GBM.

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Section: Discussionmentioning

confidence: 99%

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

et al. 2018

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“…TTK has been well characterized for its role in the spindle assembly checkpoint (SAC) complex, which prevents progression from metaphase to anaphase in mitosis when problems occur in metaphase (36)(37)(38)(39)(40). Previously, TTK inhibition has been shown to cause irregular mitosis as well as increased aneuploidy, lagging chromosomes, and mitotic catastrophe (41,42). Given these findings, previous groups have focused on TTK inhibition as a monotherapy, in combination with conventional chemotherapies, or in combination with anti-programmed cell death 1 (anti-PD-1) antibodies (18,33,41,43).…”

Section: Resultsmentioning

confidence: 99%

TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination

Chandler¹,

Moubadder²,

Ritter³

et al. 2020

Journal of Clinical Investigation

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tumor volume was calculated using the equation: volume = (length × width 2) × π/6. Additive and synergistic effects were calculated using the FTV method as previously described (59, 60). Study approval. The protocols used in this study were approved by the IACUC of the University of Michigan. Statistics. Statistical analyses were performed using GraphPad Prism 7.0 (GraphPad Software). A log-rank (Mantel-Cox) test was used for survival curve analyses. One-way ANOVA was performed for BC subtype analysis. A 2-sided Student's t test and 1-way ANOVA with Dunnett's multiple comparisons test were used for in vitro statistical analyses. A 1-way ANOVA with Dunnett's multiple comparisons test and a log-rank (Mantel-Cox) test were used for in vivo analyses. A P value of 0.05 or less was considered statistically significant.

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“…This results in mitotic segregation errors and leads to intolerable levels of genomic instability in susceptible cancer cells, ultimately leading to cell death. Several TTK inhibitors are currently being evaluated in early phase clinical trials as single agents or in combination with taxane therapy, including a compound developed by our institution's therapeutics group, CFI-402257 (Table 2) [62,63]. Additional TTK inhibitors in preclinical development include CCT271850, AZ3146, NMS-P715, MPI-0479605, CCT251455, and MPS1-IN-3, demonstrating the interest and clinical potential for this class of anti-cancer compounds [64][65][66][67][68][69][70][71].…”

Section: Ttk Inhibitorsmentioning

confidence: 99%

Targeting the cell cycle in breast cancer: towards the next phase

et al. 2018

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Deregulation of the cell cycle is a hallmark of cancer that enables limitless cell division. To support this malignant phenotype, cells acquire molecular alterations that abrogate or bypass control mechanisms in signaling pathways and cellular checkpoints that normally function to prevent genomic instability and uncontrolled cell proliferation. Consequently, therapeutic targeting of the cell cycle has long been viewed as a promising anti-cancer strategy. Until recently, attempts to target the cell cycle for cancer therapy using selective inhibitors have proven unsuccessful due to intolerable toxicities and a lack of target specificity. However, improvements in our understanding of malignant cell-specific vulnerabilities has revealed a therapeutic window for preferential targeting of the cell cycle in cancer cells, and has led to the development of agents now in the clinic. In this review, we discuss the latest generation of cell cycle targeting anti-cancer agents for breast cancer, including approved CDK4/6 inhibitors, and investigational TTK and PLK4 inhibitors that are currently in clinical trials. In recognition of the emerging population of ER+ breast cancers with acquired resistance to CDK4/6 inhibitors we suggest new therapeutic avenues to treat these patients. We also offer our perspective on the direction of future research to address the problem of drug resistance, and discuss the mechanistic insights required for the successful implementation of these strategies.

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Functional characterization of CFI-402257, a potent and selective Mps1/TTK kinase inhibitor, for the treatment of cancer

Cited by 103 publications

References 34 publications

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition

TTK inhibition radiosensitizes basal-like breast cancer through impaired homologous recombination

Targeting the cell cycle in breast cancer: towards the next phase

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