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一种靶向乳腺癌细胞和卵母细胞中MASTL-PP2A的新型MASTL抑制剂MKI-2的发现与特性研究

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

作者信息

Kang Minsung, Kim Chijung, Leem Jiyeon, Kim Ye-Hyun, Kwon Young-Ju, Yoon Yi Na, Chae Chong Hak, Ahn Jiyeon, Jung Kwan-Young, Oh Jeong Su, Kim Jae-Sung

机构信息

Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul 139-706, Korea.

Therapeutics & Biotechnology Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Korea.

出版信息

Pharmaceuticals (Basel). 2021 Jul 5;14(7):647. doi: 10.3390/ph14070647.

DOI:10.3390/ph14070647
PMID:34358073
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8308786/
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 IC 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.

摘要

尽管微管相关丝氨酸/苏氨酸激酶样蛋白（MASTL）是选择性抗癌治疗的一个有前景的靶点，但尚未有纳米级效力和抗肿瘤功效的MASTL抑制剂的报道。在此，我们报告了一种通过药物发现计划在计算机模拟中鉴定出的新型强效且选择性的MASTL抑制剂MASTL激酶抑制剂-2（MKI-2）。我们的数据表明，在乳腺癌细胞中，MKI-2抑制重组MASTL活性和细胞MASTL活性的IC值分别为37.44 nM和142.7 nM。此外，MKI-2抑制MASTL激酶而非其他AGC激酶，如ROCK1、AKT1、PKACα和p70S6K。再者，MKI-2通过诱导乳腺癌细胞中MASTL-PP2A轴调节导致的有丝分裂灾难发挥多种抗肿瘤活性。MKI-2处理在小鼠卵母细胞中表现出与MASTL基因敲除卵母细胞相似的现象，这些卵母细胞被用作验证MKI-2活性的模型。因此，我们的研究提供了一种针对乳腺癌细胞中致癌性MAST-PP2A轴的新型强效且选择性的MASTL抑制剂MKI-2。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/eef445b02d60/pharmaceuticals-14-00647-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/2be0a488b275/pharmaceuticals-14-00647-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/8fb4f86cf9cd/pharmaceuticals-14-00647-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/d495bcebb3ca/pharmaceuticals-14-00647-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/1d8cc83462ff/pharmaceuticals-14-00647-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/eef445b02d60/pharmaceuticals-14-00647-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/2be0a488b275/pharmaceuticals-14-00647-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/8fb4f86cf9cd/pharmaceuticals-14-00647-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/d495bcebb3ca/pharmaceuticals-14-00647-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/1d8cc83462ff/pharmaceuticals-14-00647-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7cf2/8308786/eef445b02d60/pharmaceuticals-14-00647-g005.jpg

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本文引用的文献

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Front Oncol. 2020 Sep 29;10:571601. doi: 10.3389/fonc.2020.571601. eCollection 2020.
2
The Greatwall kinase safeguards the genome integrity by affecting the kinome activity in mitosis.长城激酶通过影响有丝分裂中的激酶组活性来保护基因组完整性。
Oncogene. 2020 Oct;39(44):6816-6840. doi: 10.1038/s41388-020-01470-1. Epub 2020 Sep 25.
3
MASTL: A novel therapeutic target for Cancer Malignancy.
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Front Cell Dev Biol. 2022 Sep 28;10:904719. doi: 10.3389/fcell.2022.904719. eCollection 2022.
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SILAC kinase screen identifies potential MASTL substrates.SILAC 激酶筛选鉴定潜在的 MASTL 底物。
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Med Oncol. 2022 May 23;39(5):100. doi: 10.1007/s12032-022-01701-3.
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