High Proliferation Rate and a Compromised Spindle Assembly Checkpoint Confers Sensitivity to the MPS1 Inhibitor BOS172722 in Triple-Negative Breast Cancers

by Selleckchem | Nov 22 2023

BOS172722 (CCT289346) is a highly potent, selective, and orally bioavailable inhibitor of spindle assembly checkpoint kinase MPS1. BOS172722 treatment alone induces significant sensitization to death, particularly in highly proliferative triple-negative breast cancer (TNBC) cell lines with compromised spindle assembly checkpoint activity. BOS172722 synergizes with paclitaxel to induce gross chromosomal segregation defects caused by MPS1 inhibitor-mediated abrogation of the mitotic delay induced by paclitaxel treatment. In in vivo pharmacodynamic experiments, BOS172722 potently inhibits the spindle assembly checkpoint induced by paclitaxel in human tumor xenograft models of TNBC, as measured by inhibition of the phosphorylation of histone H3 and the phosphorylation of the MPS1 substrate, KNL1. This mechanistic synergy results in significant in vivo efficacy, with robust tumor regressions observed for the combination of BOS172722 and paclitaxel versus either agent alone in long-term efficacy studies in multiple human tumor xenograft TNBC models, including a patient-derived xenograft and a systemic metastasis model. The current target indication for BOS172722 is TNBC, based on their high sensitivity to MPS1 inhibition, the well-defined clinical patient population with high unmet need, and the synergy observed with paclitaxel.

Comments:

Thank you for providing this detailed information about BOS172722 and its potential in the treatment of triple-negative breast cancer (TNBC). BOS172722 appears to be a promising therapeutic agent due to its high potency, selectivity, and oral bioavailability as an inhibitor of spindle assembly checkpoint kinase MPS1.

The key points from the provided information are:

1. **Target and Mechanism of Action:** BOS172722 is an inhibitor of spindle assembly checkpoint kinase MPS1. It functions by disrupting the spindle assembly checkpoint activity in highly proliferative TNBC cells, especially those with compromised spindle assembly checkpoint function.

2. **Synergy with Paclitaxel:** BOS172722 synergizes with paclitaxel, a commonly used chemotherapy drug, to induce gross chromosomal segregation defects. This synergy is attributed to the abrogation of the mitotic delay induced by paclitaxel treatment.

3. **In Vivo Studies:** In in vivo pharmacodynamic experiments using human tumor xenograft models of TNBC, BOS172722 effectively inhibits the spindle assembly checkpoint induced by paclitaxel. This inhibition is measured by reduced phosphorylation of histone H3 and the MPS1 substrate, KNL1.

4. **Efficacy:** The synergistic effect of BOS172722 and paclitaxel leads to significant tumor regressions in long-term efficacy studies. This effect is observed in various TNBC models, including patient-derived xenografts and systemic metastasis models.

5. **Target Indication:** BOS172722 is specifically targeted for TNBC. This choice is based on the high sensitivity of TNBC cells to MPS1 inhibition, the presence of a clinically well-defined patient population with high unmet medical needs, and the observed synergy with paclitaxel.

It's important to note that this information provides a strong rationale for further exploration of BOS172722 in clinical trials for TNBC treatment, given its promising preclinical results. Clinical trials would be necessary to determine its safety and efficacy in human patients and to potentially bring this treatment option to the clinic.