Dual specificity protein kinase TTK (MPS1) (TTK)

Dual specificity protein kinase TTK (MPS1) is a vital enzyme that regulates the spindle assembly checkpoint (SAC) to ensure accurate chromosome segregation during mitosis [1.1.3, 1.2.1]. It functions by phosphorylating various substrates at the kinetochore, preventing the transition to anaphase until all chromosomes are correctly attached to the spindle microtubules [1.2.5, 1.3.4]. Beyond its role in the SAC, TTK is involved in centrosome duplication and the DNA damage response, making it a central player in maintaining genomic stability [1.1.4, 1.2.2]. TTK is frequently overexpressed in a wide range of human cancers, including triple-negative breast cancer and non-small cell lung cancer, where its high levels are often associated with poor prognosis and increased chromosomal instability [1.2.4, 1.4.2]. This overexpression makes it an attractive therapeutic target, as inhibiting TTK activity can force cancer cells into premature mitotic exit, leading to catastrophic aneuploidy and apoptosis [1.3.2, 1.4.1]. Several small-molecule TTK inhibitors, such as CFI-402257 and BAY 1217389, have entered clinical trials, primarily for the treatment of advanced solid tumors [1.3.2, 1.3.3]. These drugs aim to exploit the vulnerability of cancer cells to mitotic disruption, often in combination with other antineoplastic agents to enhance efficacy and overcome resistance [1.3.3, 1.3.4].

Other names

Monopolar spindle 1 kinaseMPS1MPH1PYTCT96Cancer/Testis Antigen 96ESKPhosphotyrosine picked threonine kinaseMPS1L1

Inhibition of TTK/MPS1 kinase activity, leading to spindle assembly checkpoint abrogation, premature mitotic exit, and mitotic catastrophe [1.3.2, 1.3.4].