Mitotic Checkpoint Targeting with OSU-13: A Promising Therapeutic Approach for High-Risk Myeloma

Despite recent progress, there is an ongoing need for new treatments for patients with high-risk multiple myeloma (MM). The protein Monopolar spindle 1 (Mps1), also referred to as TTK protein kinase, plays a critical role in the mitotic spindle checkpoint and centrosome duplication, and is implicated in aneuploidy, a characteristic of cancer cells. Studies have shown that elevated levels of MPS1 are associated with a negative prognosis in certain cancers.

This study focused on the role of Mps1 in MM and examined the effects of a new inhibitor, OSU-13. The analysis of a database revealed that increased MPS1 expression is linked to reduced overall and event-free survival in MM patients and is particularly prevalent in those with specific genetic alterations.

Comparative expression studies between MM cell lines and primary cells from MM patients showed higher levels of MPS1 in all MM cell lines. The novel inhibitor OSU-13 was found to effectively inhibit Mps1-NanoLuc binding with an EC50 of 10 nM, which is significantly lower than other agents.

Cytotoxicity assays using the MTT method demonstrated that OSU-13 had a significant impact on the viability of MM cell lines, with OPM-2 being the most sensitive. Further investigation into the cell death mechanisms induced by OSU-13 showed an increase in Annexin V staining, indicating apoptosis, and caspases 3/7 activation, which peaked after 72 hours of treatment.

In vivo studies using a H929 MM xenograft model in mice showed that treatment with OSU-13 resulted in a significant delay in tumor growth. These findings suggest that targeting the mitotic checkpoint with OSU-13 could be a promising therapeutic approach for high-risk MM.