Targeting Mps1 Kinase: Unveiling the Potential of Novel Inhibitors in Tumor Suppression

The cell cycle's irregular functioning is a key feature of cancer, with cell cycle interruption being a common strategy for many anti-cancer drugs like taxanes and vinca alkaloids. A new cancer treatment approach involves targeting cell cycle checkpoints, which can lead to tumor cells undergoing aneuploidy and death due to uncontrolled mitosis despite DNA damage or improper chromosome attachment.

Mps1, a mitotic enzyme overexpressed in some cancers and crucial for activating the spindle assembly checkpoint (SAC), is highlighted in this research. The study introduces two new Mps1 inhibitors, BAY 1161909 and BAY 1217389, which belong to different chemical families. Both inhibitors effectively reduced Mps1 activity with low IC50 values and showed high selectivity among various kinases.

In cellular tests, these inhibitors disrupted the SAC activity caused by nocodazole, leading to an early exit from mitosis and subsequent cell death due to multinucleation. They also significantly hindered the proliferation of various tumor cell lines in vitro and showed moderate efficacy in monotherapy within tumor xenograft studies.

When combined with paclitaxel, these Mps1 inhibitors demonstrated an enhanced effect, overcoming both intrinsic and acquired resistance to paclitaxel. Importantly, they did not increase the toxicity associated with paclitaxel treatment.

The research supports the innovative strategy of SAC inhibition and suggests that combining Mps1 inhibitors with other anti-cancer drugs could improve effectiveness and potentially counteract drug resistance. BAY 1161909 is currently undergoing a phase I clinical trial, and plans are in place to initiate trials for BAY 1217389. These are the first Mps1 inhibitors to enter clinical trials.

Reference: Wengner AM, et al. Novel Mps1 kinase inhibitors with potent anti-tumor activity. Cancer Res 2015;75(15 Suppl):Abstract nr 3090.