Discovery and Characterization of a Novel MASTL Inhibitor MKI-2 Targeting MASTL-PP2A in Breast Cancer Cells and Oocytes
- Pharmaceuticals (Basel). 2021 Jul 5;14(7):647. doi: 10.3390/ph14070647.
- 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.
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.