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

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.