Furthermore, MPH-5 showed potent inhibition of HepG2 xenograft tumor growth in mice with no apparent toxicity and presented favorable pharmacokinetics. The study suggests that MPH-5 is a potent, selective, high-efficacy, and low-toxicity antitumor candidate for the treatment of hepatocellular carcinoma.

P1/2, N=31, Completed, Nerviano Medical Sciences | Active, not recruiting --> Completed | Trial completion date: Mar 2025 --> Aug 2024

P1, N=216, Recruiting, SillaJen, Inc. | N=120 --> 216

P1/2, N=37, Active, not recruiting, Canadian Cancer Trials Group | Phase classification: P2 --> P1/2 | Trial completion date: Dec 2023 --> Dec 2024

Combining a low-toxicity dose of OSU13 with anti-PD1 checkpoint blockade resulted in prominent STING- and CD8 T cell-dependent tumor inhibition and improved survival. These findings provide a rationale for utilizing TTK inhibitors in combination with immunotherapy in STING-proficient tumors.

P1, N=120, Recruiting, SillaJen, Inc. | Trial primary completion date: Sep 2024 --> Jul 2025

Interestingly, patients with high expression of SMAD3 exhibited significant resistance to dasatinib and staurosporine, while high sensitivity to tamoxifen and auranofin. In addition, SMAD3 knockdown promoted the apoptosis of BT-549 cells and decreased cell activity, and BAY-1161909 and XK-469 increased drug efficacy. In conclusion, genes of the SMAD family play a crucial role in the development of breast cancer.

P1/2, N=31, Active, not recruiting, Nerviano Medical Sciences | Recruiting --> Active, not recruiting | N=57 --> 31 | Trial completion date: Mar 2026 --> Mar 2025 | Trial primary completion date: Nov 2025 --> Jan 2024

Antimitotic compounds, targeting key spindle assembly checkpoint (SAC) components (e.g., MPS1, Aurora kinase B, PLK1, KLP1, CENPE), are potential alternatives to microtubule-targeting antimitotic agents (e.g., paclitaxel) to circumvent resistance and side effects associated with their use...We investigated the impact of inhibiting anti-apoptotic signals with the BH3-mimetic navitoclax in lung cancer cells treated with the selective CENPE inhibitor GSK923295 (mitotic blocker) or the MPS1 inhibitor BAY1217389 (mitotic driver)...Crucially, these synergistic concentrations were less toxic to non-tumor cells. This highlights the significance of combining BH3-mimetics with antimitotics, either blockers or drivers, which have reached the clinical trial phase, to enhance their effectiveness.

P1/2, N=44, Recruiting, Treadwell Therapeutics, Inc

Moreover, TTK inhibition also upregulated the expression of PD-L1, demonstrating a synergistic effect with anti-PD1 therapy in 4T1 tumor-bearing mice. Taken together, TTK inhibition facilitated anti-tumor immunity mediated by T cells and enhanced sensitivity to PD-1 blockade, providing a rationale for the combining TTK inhibitors with immune checkpoint blockade in clinical trials.

CFI-402257 is a potent inhibitor of TTK. It is well tolerated with manageable TEAEs, no dose limiting or treatment limiting toxicities, and no treatment related deaths. Dose expansion in the patient population of interest will commence.

In vivo, OSU-13 decreased tumor growth in mice with NCI-H929 xenografts. Collectively, our findings reveal that inhibiting TTK with OSU-13 is a potential therapeutic strategy for MM, particularly for a subset of high-risk patients with poor outcome.

The fate of tumor cells after SAC abrogation is driven by an AURKB/ CASP-2 signaling mechanism, regulated by BID levels. Our results pave the way to clinically explore SAC-targeting drugs in tumors with high BID expression.

P1/2, N=57, Recruiting, Nerviano Medical Sciences | Trial completion date: Mar 2027 --> Mar 2026 | Trial primary completion date: Nov 2026 --> Nov 2025

An in vitro cytotoxicity study showed the potential suppression of MCF-7 cells with IC values of 11.7 ± 0.04 and 6.6 ± 0.01 μg mL for compounds 1 and 2, respectively, compared to doxorubicin (IC = 3.83 ± 0.01 μg mL)...Moreover, molecular docking analysis, which was performed against the anticancer mitotic (or spindle assembly) checkpoint target Mps1 kinase, showed that the two new cyclic glycolipids (1 and 2) possess high binding affinity of -7.7 and - 7.6 kcal mol, respectively, compared to its ATP ligand. Overall, this report emphasizes that natural cyclic glycolipids can be used as potential antitumour breast cancer agents.

P2, N=37, Active, not recruiting, Canadian Cancer Trials Group | Trial primary completion date: Jun 2023 --> Nov 2022

This increase was induced by treatment with CFI-402257, a selective inhibitor of the mitotic kinase TTK, which plays a key role in spindle-assembly checkpoint (SAC) regulation...Overall, these results suggest that GSCs have an enhanced ability to tolerate the negative consequences of aneuploidy on survival as well as on radiosensitivity. Such aneuploid tolerance may provide a mechanism through which GBMs exploit karyotype diversity to survive under harsh environmental conditions and after treatment.

Tumor growth was monitored and, following the completion of the study, final tumor weights were recorded and tumor tissue was collected to perform immunofluorescent microscopy. Single-agent TTK inhibition via treatment with the ATP-competitive inhibitor empesertib inhibits the growth of murine TNBC cell lines with IC50 values up to 30nM... Our data suggests that TTK inhibition and radiotherapy is synergistic in murine TNBC and alters the tumor immune microenvironment. This combined therapy suggests that changes in the underlying immune mechanisms as a result of the synergistic treatment efficacy are important in TNBC. Future work will examine the underlying mechanisms of TTK inhibition and radiotherapy on systemic and tumoral immune changes.

Further studies are ongoing to evaluate the underlying mechanisms.Our data suggest that gastric cancer is sensitive to the Mps1 inhibitor, resulting in cell growth suppression. It may provide new potent treatment options for GC patients.

TTK inhibits apoptosis through AKT-mTOR pathway, worsening ovarian cancer. And TTK was also one significant hub biomarker of renal cancer.

Our findings establish the clinical significance of TTK as a new biomarker for EC and an as-yet-unknown carcinogenic function. This present study proposes that the therapeutic targeting of TTK might provide a viable approach for the treatment of EC.

The findings suggest that the TTK inhibitor could be used in EC therapy. This study highlighted the potential predictive role of TTK molecules and showed that TTK molecules might serve as prospective targets for EC therapy.

This new class of molecularly targeted radiosensitizing agents is being evaluated in preclinical and clinical studies to monitor their activity in potentiating radiation cytotoxicity of tumors and reducing normal tissue toxicity. The molecular pathways of DNA damage response are reviewed with a focus on the repair mechanisms, therapeutic targets under current clinical evaluation including ATM, ATR, CDK1, CDK4/6, CHK1, DNA-PKcs, PARP-1, Wee1, & MPS1/TTK and potential new targets (BUB1, and DNA LIG4) for radiation sensitization.

TTK correlated with all of the clinical variables but p-TBK1 did not correlate with any of them. TCGA analysis revealed that the mRNA levels of multiple mitotic kinases, including TTK, Nek2, Plk1, Bub1, and Aurora kinases A and B, and transcription factors that are known to control the expression of these kinases (e.g. FoxM1 and E2F1-3) were upregulated in NHBs versus NHWs and correlated with higher aneuploidy indexes in NHB, suggesting that these mitotic kinases may be future novel targets for breast cancer treatment in NHB women.

Similarly, MM/PBSA method based free energy calculations showed that these compounds bind with reasonably good affinity to the TTK protein. Overall molecular modelling results suggest that newly designed compounds can act as lead compounds for the optimization of TTK inhibitors.

The few available therapies for mCRPC include the Taxanes Docetaxel (DTX) and Cabazitaxel (CBZ). Overall, our data demonstrate that forced mitotic exit by Mps1 inhibition potentiates Taxanes efficacy. Given that several Mps1i's are currently in different stages of clinical trials, our results point to Mps1 as a new therapeutic target to potentiate efficacy of Taxanes in mCRPC patients.

In this issue of Cancer Cell, Kitajima et al. outline a strategy to unleash innate immunity in KL tumors by utilizing epigenetic de-repression of STING and pulsed inhibition of spindle assembly checkpoint kinase MPS1.

This effect is markedly amplified by epigenetic de-repression of STING and only requires pulse MPS1i treatment, creating a therapeutic window compared with non-dividing cells. A single course of decitabine treatment followed by pulse MPS1i therapy restores T cell infiltration in vivo, enhances anti-PD-1 efficacy, and results in a durable response without evidence of significant toxicity.

Background: TTK (also known as MPS1), a dual-specificity serine-threonine kinase, is critical for the spindle assembly checkpoint, chromosome alignment, and error correction in mitosis. CFI- 402257 is well tolerated as mono and combination with fulvestrant. Efficacy signals are emerging with pts in the combo cohort demonstrating anti-tumor activity. Additional efficacy will be updated at the time of the presentation.

CFI-402257 and paclitaxel was well tolerated, with neutropenia as the main toxicity. DL3 (168mg) was selected as RP2D. Phase 2 ORR and CBR was 5.9% and 58.8%, respectively; during Phase 2, the 17 evaluable patients from stage 1 did not meet the pre-specified threshold for anti-tumor activity to proceed to stage 2 and the trial was closed to accrual on April 7, 2022.

NudCD1 can serve as a valuable prognostic marker for colorectal cancer. It may be involved in the regulation of spindle-assembly checkpoint-gene expression and the LIS1 pathway of colorectal cancer cells.

In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER breast cancer patients who develop resistance to CDK4/6i.

BAL0891 combined with paclitaxel in vivo showed strong reproducible synergy in the TNBC BR1282 model, with a high percentage of complete cures. Synergistic anti-tumor effects were also observed with carboplatin in the ovarian SKOV-3 model. Strong BAL0891 single agent activity was previously reported; the current data support BAL0891 combination strategies in the clinic.

Further, CFI-402257 improved survival in HCC-bearing mice treated with anti-PD-1, suggesting the possibility of combination treatment with immune checkpoint inhibitors in HCC patients. In summary, our study characterized CFI-402257 as a potential therapeutic for HCC, both used as a single agent and in combination therapy.

P1/2, N=44, Recruiting, Treadwell Therapeutics, Inc | Not yet recruiting --> Recruiting

We demonstrated that TTK promotes the TMZ resistance of GBM cells by inducing autophagy in vitro and in vivo. The use of a TTK inhibitor in combination with TMZ might help to overcome TMZ resistance and improve therapy efficiency in GBM.

More importantly, in vivo targeting GRP75 combined with cell-cycle or macropinocytosis inhibitors exhibited distinct suicide gene therapy efficiency. In summary, our data highlight that mitochondrial chaperone GRP75 moonlights as a biphasic driver underlying cell-cycle-dependent macropinocytosis of Tat/pDNA-Ca nanoparticles in ovarian cancer.

P1, N=52, Active, not recruiting, University Health Network, Toronto | Recruiting --> Active, not recruiting | Trial completion date: Jan 2022 --> May 2027 | Trial primary completion date: Jan 2022 --> May 2027

Safety endpoints include incidence of treatment emergent adverse events. Exploratory objectives include characterization of protein and molecular alterations relevant to the cell cycle and CFI-402257 response.