Discovery of IHMT-MST1-58 as a Novel, Potent, and Selective MST1 Inhibitor for the Treatment of Type 1/2 Diabetes

  • J Med Chem. 2022 Sep 8;65(17):11818-11839. doi: 10.1021/acs.jmedchem.2c00926.
Yun Wu  1  2 ,  Ziping Qi  1  2 ,  Beilei Wang  1  2 ,  Junjie Wang  1  3 ,  Qingwang Liu  1  2 ,  Aoli Wang  1  2 ,  Chenliang Shi  1  3 ,  Bin Zhou  1  3 ,  Qianmao Liang  1  3 ,  Wenliang Wang  1  4 ,  Fengming Zou  1  2 ,  Shuang Qi  1  2 ,  Zuowei Wang  1  3 ,  Li Wang  1  2 ,  Wenchao Wang  1  2  3 ,  Jing Liu  1  2  3 ,  Qingsong Liu  1  2  3  4
Affiliations
  • 1. Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
  • 2. Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui 230031, P. R. China.
  • 3. University of Science and Technology of China, Hefei, Anhui 230026, P. R. China.
  • 4. Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui 230088, P. R. China.
PMID: 36037148 DOI: 10.1021/acs.jmedchem.2c00926
Abstract

The critical pathogenesis of type 1 diabetes (T1D)/type 2 diabetes (T2D) is the physical status, mass, and function of pancreatic β cells. Mammalian STE20-like protein 1 kinase (MST1) plays vital roles in the Apoptosis and Insulin secretion of β cells. Here, we discovered a novel, potent, and selective MST1 inhibitor 19 (IC50 = 23 nM), which inhibited the phosphorylation of MST1-protected β cells from the damage of inflammatory cytokines in vitro. In vivo, it displayed acceptable pharmacokinetic properties in different species. In the STZ-induced T1D/T2D mouse models, both monotherapy of 19 and in combination with metformin led to the decline of fasting blood glucose and showed protective effect of β cells. In addition, the combination of 19 and metformin decreased the Hemoglobin A1c level. Together, our study suggested that 19 might be a useful pharmacological tool to study MST1-mediated physiology and pathology as well as a potential drug candidate for diabetes.

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