Discovery and Characterization of a Novel MASTL Inhibitor MKI-2 Targeting MASTL-PP2A in Breast Cancer Cells and Oocytes

被引:7
作者
Kang, Minsung [1 ]
Kim, Chijung [2 ]
Leem, Jiyeon [3 ]
Kim, Ye-hyun [1 ]
Kwon, Young-ju [1 ,4 ]
Yoon, Yi Na [1 ]
Chae, Chong Hak [2 ]
Ahn, Jiyeon [1 ]
Jung, Kwan-Young [2 ,5 ]
Oh, Jeong Su [3 ]
Kim, Jae-Sung [1 ,4 ]
机构
[1] Korea Inst Radiol & Med Sci, Div Radiat Biomed Res, Seoul 139706, South Korea
[2] Korea Res Inst Chem Technol, Therapeut & Biotechnol Div, Daejeon 34114, South Korea
[3] Sungkyunkwan Univ, Dept Integrat Biotechnol, Suwon 16419, South Korea
[4] Univ Sci & Technol, Radiol & Med Oncol Sci, Daejeon 34113, South Korea
[5] Univ Sci & Technol, Dept Med Chem & Pharmacol, Daejeon 34113, South Korea
基金
新加坡国家研究基金会;
关键词
MASTL; MASTL inhibitor; PP2A; antitumor activity; breast cancer; PROTEIN PHOSPHATASE 2A; GREATWALL KINASE; MITOSIS; PROGRESSION; CIP2A;
D O I
10.3390/ph14070647
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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, PKAC alpha, 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.
引用
收藏
页数:12
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