Dysregulation of the cell cycle stands as a pivotal hallmark in the realm of tumor cells [[1], [2], [3]]. Molecular targets related to cell cycle inhibition deserve special attention because they are potentially therapeutic agents to regulate abnormal cell proliferation [4,5]. Monopolar spindle 1 (MPS1), alternatively recognized as threonine tyrosine kinase (TTK), coordinates key events during mitosis and has received widespread attention due to its overexpression in various cancer types [[6], [7], [8]]. MPS1's involvement in the regulation of cell mitosis makes it a high-profile candidate molecule in the anti-cancer drug development [9,10], its applications include triple-negative breast cancer (TNBC) [[11], [12], [13], [14]], pancreatic ductal adenocarcinoma cells, lung cancer cell lines, among others [15,16]. MPS1 protein kinase is an indispensable dynamic enzyme throughout cellular proliferation, directly influencing cell growth and proliferation by regulating kinase activity, chromosomal stability, and cell cycle progression [17,18], Furthermore, MPS1 overexpression leads to the deregulation of cell cycle checkpoints and chromosome stability [19], contributing to the unbridled proliferation of cancer cells [[20], [21], [22]]. Given the instability of cancer cells, inhibiting MPS1 kinase proves beneficial in impeding cancer cell division and consequently suppressing tumor growth [[23], [24], [25]].

At present, clinical phases I/II have witnessed the advancement of six small molecule inhibitors targeting MPS1: CFI-402257 (1) [[26], [27], [28], [29]], BAY-1161909 (2) (discontinued) [30,31], BAY-1217389 (3) [[32], [33], [34]], BOS-172722 (4) [[35], [36], [37]], S-81694 [38,39] and BAL-0891 [40,41], marking a promising advance in the quest for effective cancer treatments (Table 1). Despite the notable efficacy demonstrated by these compounds in preclinical studies, nearly all clinical investigations have involved their combination with the microtubule-targeting drug paclitaxel. Co-administration with paclitaxel has been shown to elicit synergistic effects, thereby enhancing therapeutic efficacy and overcoming paclitaxel resistance. This pattern suggests that research on MPS1 inhibitors still faces several challenges. Consequently, an urgent imperative emerges to explore novel, efficient, and specific MPS1 inhibitors tailored for targeted cancer treatments.

This perspective examines the recent advancements in MPS1 inhibitors over the past decade. We offer a comprehensive overview of the design strategy, structural optimization, structure-activity relationship studies, selectivity, and pharmacokinetic characteristics of each inhibitor, focusing on the perspective of medicinal chemistry. The systematic summary presented herein offers crucial insights for researchers working towards developing novel and highly effective small molecule MPS1 inhibitors for anticancer applications.