Design, synthesis, and evaluation of novel thieno[2,3-b]pyridine derivatives as DRAK2 inhibitors

  • Eur J Med Chem. 2026 Jun 3:316:119033. doi: 10.1016/j.ejmech.2026.119033.
Yuhang Shu  1 ,  Bingqian Zhang  2 ,  Yuxin Zhang  2 ,  Xinwen Zhang  3 ,  Honghong Xu  3 ,  Ruihan Li  4 ,  Yuhong Liu  3 ,  Yueqing Zhang  1 ,  Maoqian Xiong  1 ,  Jie Tang  1 ,  Yuting Lu  5 ,  Jingya Li  6 ,  Fan Yang  7
Affiliations
  • 1. School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, the National Center for Drug Screening, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, the National Center for Drug Screening, Shanghai, 201203, China.
  • 4. The First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, the National Center for Drug Screening, Shanghai, 201203, China. Electronic address: [email protected].
  • 6. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, the National Center for Drug Screening, Shanghai, 201203, China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, China. Electronic address: [email protected].
  • 7. School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, China. Electronic address: [email protected].
PMID: 42251818 DOI: 10.1016/j.ejmech.2026.119033
Abstract

DRAK2 (STK17B), a serine/threonine kinase, functions as a positive regulator of Apoptosis. Despite its therapeutic potential, pharmacological inhibition of DRAK2 remains underexplored. To address this gap, we leveraged the previously disclosed small-molecule DRAK2 inhibitor 22b as a chemical starting point and designed, synthesized, and evaluated a novel series of thieno[2,3-b]pyridine derivatives. Through systematic structure-activity relationship (SAR) analysis, compound I14 was identified as a lead DRAK2 inhibitor with favorable bioactivity. It exhibited improved DRAK2 inhibitory potency (IC50 = 198.5 nM) relative to the reference compound 22b; enhanced glucose-stimulated Insulin secretion (GSIS) in mouse pancreatic islets by 1.86-fold (low dose) and 1.72-fold (high dose); elevated mitochondrial membrane potential (MMP) in INS-1E cells by 1.08-fold and 1.10-fold, respectively; and mitigated palmitic acid (PA)-induced MMP impairment and Apoptosis. In vivo, I14 significantly improved glucose tolerance in an oral glucose tolerance test (OGTT). Mechanistically, I14 exerted its efficacy through modulation of the DRAK2-ULK1 signaling axis which was well established in our previous study. Molecular docking analyses further supported its target engagement, revealing stable hydrogen-bond interactions with Ala113 and Lys37 within the DRAK2 ATP-binding pocket. Collectively, these findings identify I14 as the first orally efficacious, mechanism-validated DRAK2 inhibitor with translational relevance for type 2 diabetes (T2D) therapy.

Keywords
DRAK2; Diabetes; Inhibitor; Pancreatic β cell.
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