Discovery of IHMT-MST1-39 as a novel MST1 kinase inhibitor and AMPK activator for the treatment of diabetes mellitus

Signal Transduct Target Ther. 2023 Apr 5;8(1):143. doi: 10.1038/s41392-023-01352-4.

Junjie Wang ^# ¹ ², Ziping Qi ^# ¹ ³, Yun Wu ^# ¹ ³, Aoli Wang ^# ¹ ³, Qingwang Liu ¹ ³, Fengming Zou ¹ ³, Beilei Wang ¹ ³, Shuang Qi ¹ ³, Jiangyan Cao ¹ ², Chen Hu ¹ ³, Chenliang Shi ¹ ², Qianmao Liang ¹ ², Li Wang ¹ ³, Jing Liu ⁴ ⁵, Wenchao Wang ⁶ ⁷, Qingsong Liu ⁸ ⁹ ¹⁰ ¹¹

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 University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China.
3 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China.
4 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. [email protected].
5 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China. [email protected].
6 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. [email protected].
7 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China. [email protected].
8 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. [email protected].
9 University of Science and Technology of China, Hefei, Anhui, 230026, P. R. China. [email protected].
10 Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei, Anhui, 230031, P. R. China. [email protected].
11 Precision Medicine Research Laboratory of Anhui Province, Hefei, Anhui, 230088, P. R. China. [email protected].
# Contributed equally.

PMID: 37015918 DOI: 10.1038/s41392-023-01352-4

Abstract

Insulin-producing pancreatic β cell death is the fundamental cause of type 1 diabetes (T1D) and a contributing factor to type 2 diabetes (T2D). Moreover, metabolic disorder is another hallmark of T2D. Mammalian sterile 20-like kinase 1 (MST1) contributes to the progression of diabetes mellitus through Apoptosis induction and acceleration of pancreatic β cell dysfunction. AMP-activated protein kinase (AMPK) is an energy sensing kinase and its activation has been suggested as a treatment option for metabolic diseases. Thus, pharmacological inhibition of MST1 and activation of AMPK simultaneously represents a promising approach for diabetes therapy. Here, we discovered a novel selective MST1 kinase inhibitor IHMT-MST1-39, which exhibits anti-apoptosis efficacy and improves the survival of pancreatic β cells under diabetogenic conditions, as well as primary pancreatic islets in an ex vivo disease model. Mechanistically, IHMT-MST1-39 activated AMPK signaling pathway in hepatocytes in vitro, combination of IHMT-MST1-39 and metformin synergistically prevented hyperglycemia and significantly ameliorated glucose tolerance and Insulin resistance in diabetic mice. Taken together, IHMT-MST1-39 is a promising anti-diabetic candidate as a single agent or in combination therapy for both T1D and T2D.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-164595

IHMT-MST1-39

99.68%, MST Inhibitor

Hippo (MST); Apoptosis; AMPK

Metabolic Disease

Name
Email *

	Sorry, but the email address you supplied was invalid.