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Abstract
Although microtubule-associated serine/threonine kinase-like (MASTL) is a promising target for selective anticancer treatment, MASTL inhibitors with nano range potency and antitumor efficacy have not been reported. Here, we report a novel potent and selective MASTL inhibitor MASTL kinase inhibitor-2 (MKI-2) identified in silico through a drug discovery program. Our data showed that MKI-2 inhibited recombinant MASTL activity and cellular MASTL activity with IC50 values of 37.44 nM and 142.7 nM, respectively, in breast cancer cells. In addition, MKI-2 inhibited MASTL kinase rather than other AGC kinases, such as ROCK1, AKT1, PKACα, and p70S6K. Furthermore, MKI-2 exerted various antitumor activities by inducing mitotic catastrophe resulting from the modulation of the MASTL-PP2A axis in breast cancer cells. The MKI-2 treatment showed phenocopies with MASTL-null oocyte in mouse oocytes, which were used as a model to validate MKI-2 activity. Therefore, our study provided a new potent and selective MASTL inhibitor MKI-2 targeting the oncogenic MAST-PP2A axis in breast cancer cells.

Affiliations

Minsung Kang  1 , Chijung Kim  2 , Jiyeon Leem  3 , Ye-Hyun Kim  1 , Young-Ju Kwon  1   4 , Yi Na Yoon  1 , Chong Hak Chae  2 , Jiyeon Ahn  1 , Kwan-Young Jung  2   5 , Jeong Su Oh  3 , Jae-Sung Kim  1   4
1 Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.
2 Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea.
3 Department of Integrative Biotechnology, Sungkyunkwan University, Suwon 16419, Korea.
4 Radiological and Medico-Oncological Sciences, University of Science and Technology, Daejeon 34113, Korea.
5 Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon 34113, Korea.