Molecular design and anticancer activities of small-molecule monopolar spindle 1 inhibitors: A Medicinal chemistry perspective

As a dual-specificity protein kinase, monopolar spindle 1 (Mps1) is one of the main kinases involved in kinetochore localization and the spindle assembly checkpoint (SAC). Cancer cells often display chromosomal instability, which is a consequence of disfunction of cell cycle checkpoints partially. Mps1 is overexpressed in multiple cancer types to face the pressure from aberrant chromosomes and centrosomes. Therefore, Mps1 is a potential targeting approach to cancer treatment. Several compounds targeting Mps1 have been developed and approved to begin clinical trials for advanced nonhaematologic malignancies treatments, including but not limited to triple negative breast cancer (TNBC) treatment. In this review, we will highlight typical Mps1 inhibitors developed during the last decade and provide a reference for more potential Mps1 inhibitors exploration in the future. [Display omitted] •Mps1 plays a very important role in cell division, and its expression in solid tumors is much higher than in normal cells.•Mps1 is a novel and promising target for cancer therapy, and only five small-molecule inhibitors have entered clinical trials to date.•Some Mps1 inhibitors are not only to target the excess Mps1 in tumors with little impact on normal cells, but also enhance the sensitivity of cancer cell lines combined with chemotherapeutic drugs, such as paclitaxel.•This review mainly describes the design, structure characteristics and bioactivities of Mps1 inhibitors. The efficacy, selectivity, resistances, pharmacokinetics and secondary effects are also analysed.