Molecular mechanism of point mutation-induced Monopolar spindle 1 (Mps1/TTK) inhibitor resistance revealed by a comprehensive molecular modeling study.

ABSTRACT:

Background

Monopolar spindle 1 (Mps1/TTK) is an apical dual-specificity protein kinase in the spindle assembly checkpoint (SAC) that guarantees accurate segregation of chromosomes during mitosis. High levels of Mps1 are found in various types of human malignancies, such as glioblastoma, osteosarcoma, hepatocellular carcinoma, and breast cancer. Several potent inhibitors of Mps1 exist, and exhibit promising activity in many cell cultures and xenograft models. However, resistance due to point mutations in the kinase domain of Mps1 limits the therapeutic effects of these inhibitors. Understanding the detailed resistance mechanism induced by Mps1 point mutations is therefore vital for the development of novel inhibitors against malignancies.

Methods

In this study, conventional m

SUBMITTER: Han Y 

PROVIDER: S-EPMC6345219 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature