2. Academic Validation
  3. Novel thieno[2,3-b]pyridine derivatives protect islet through DRAK2 kinase inhibition

Novel thieno[2,3-b]pyridine derivatives protect islet through DRAK2 kinase inhibition

  • Eur J Med Chem. 2026 Jan 5:301:118258. doi: 10.1016/j.ejmech.2025.118258.
Kaiyue Lian 1,  Ruihan Li 2,  Yuting Lu 3,  Gaolei Song 3,  Xinwen Zhang 3,  Yuxin Zhang 1,  Honghong Xu 3,  Xinyu Sun 3,  Min Gu 3,  Yang Yang 4,  Hui Ma 3,  Jingya Li 5,  Fajun Nan 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 2 The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 3 State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 4 State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 5 State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, 310024, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Drug Research, The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, Shandong, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
PMID: 41109008 DOI: 10.1016/j.ejmech.2025.118258
Abstract

DRAK2 (STK17B), a serine/threonine kinase, plays a critical role in Apoptosis and has been implicated in metabolic diseases, including type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH). Previous studies have demonstrated DRAK2's roles in pancreatic β cell dysfunction and mitochondrial impairment. This study is dedicated to the development of novel DRAK2 inhibitors aimed at preserving β cell function. Through comprehensive structure-activity relationship (SAR) analyses, we synthesized and evaluated a series of compounds, identifying potent inhibitors (represented by Y17) with nanomolar potency. In vitro experiments revealed that these compounds enhanced mitochondrial membrane potential (MMP) in INS-1E cells and glucose-stimulated Insulin secretion (GSIS) in primary mouse islets, as well as protecting against palmitic acid (PA)-induced Apoptosis. In vivo studies demonstrated the distribution of the compounds in pancreatic tissue and their ability to improve glucose tolerance in mice. Molecular docking analyses elucidated key interactions between the inhibitors and DRAK2. The inhibitors exerted their function particularly via the DRAK2-ULK1 axis, thereby confirming their mechanism of action. Collectively, our findings underscore DRAK2 as a promising therapeutic target for T2D and provide a potential for developing antidiabetic therapies through preserving β cell function.

Keywords

DRAK2; Diabetes; Inhibitor; Thieno[2,3-b]pyridine.

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