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

Area of Science:

• Biochemistry
• Molecular Biology
• Endocrinology

Background:

• DRAK2 (STK17B) is a kinase involved in apoptosis and linked to metabolic diseases like type 2 diabetes (T2D) and metabolic dysfunction-associated steatohepatitis (MASH).
• Previous research indicates DRAK2's involvement in pancreatic beta cell dysfunction and mitochondrial impairment, crucial factors in T2D pathogenesis.

Purpose of the Study:

• To develop novel inhibitors targeting DRAK2 (STK17B) to preserve pancreatic beta cell function.
• To identify potent DRAK2 inhibitors through structure-activity relationship (SAR) analyses for potential antidiabetic therapies.

Main Methods:

• Synthesis and evaluation of DRAK2 inhibitors using SAR analyses.
• In vitro assays assessing mitochondrial membrane potential (MMP), glucose-stimulated insulin secretion (GSIS), and apoptosis protection.
• In vivo studies in mice to evaluate glucose tolerance and compound distribution.
• Molecular docking to elucidate inhibitor-target interactions.

Main Results:

• Identification of potent DRAK2 inhibitors (e.g., Y17) with nanomolar potency.
• In vitro: Compounds enhanced MMP in INS-1E cells, improved GSIS in primary mouse islets, and protected against palmitic acid-induced apoptosis.
• In vivo: Compounds distributed to pancreatic tissue and improved glucose tolerance in mice.
• Mechanism confirmed via DRAK2-ULK1 axis interaction.

Conclusions:

• DRAK2 is a viable therapeutic target for T2D.
• Novel DRAK2 inhibitors demonstrate potential for preserving beta cell function and developing new antidiabetic treatments.