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

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.