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

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.
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
Affiliations

Affiliations

  • 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.
PMID: 34358073 DOI: 10.3390/ph14070647
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.

Keywords

MASTL; MASTL inhibitor; PP2A; antitumor activity; breast cancer.

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