Allosteric MAPKAPK2 inhibitors improve plaque stability in advanced atherosclerosis

Area of Science:

• Biochemistry
• Pharmacology
• Cardiovascular Disease

Background:

• Atherosclerotic vascular disease is a primary cause of death in type 2 diabetes (T2D).
• Unstable atherosclerotic plaques contribute significantly to morbidity and mortality in T2D patients.
• Mitogen-activated protein kinase-activated protein kinase-2 (MK2) inhibition shows promise for improving glucose homeostasis and insulin sensitivity.

Purpose of the Study:

• To evaluate the effects of novel MK2 inhibitors (TBX-1 and TBX-2) on metabolism and atherosclerosis.
• To assess the potential of MK2 inhibitors as a therapeutic strategy for T2D-associated cardiovascular complications.

Main Methods:

• Development of two orally active small-molecule MK2 inhibitors, TBX-1 and TBX-2.
• Administration of TBX-1 or TBX-2 to high-fat Western diet-fed Ldlr-/- mice with established atherosclerotic lesions.
• Assessment of metabolic parameters (glucose metabolism, plasma lipids, body weight) and atherosclerotic plaque characteristics (lesion area, necrosis, fibrous cap thickness).

Main Results:

• Both TBX-1 and TBX-2 improved glucose metabolism and reduced plasma cholesterol and triglycerides without affecting body weight.
• The MK2 inhibitors significantly decreased atherosclerotic lesion area in the aortic root.
• Treatment with TBX-1 and TBX-2 reduced plaque necrosis and increased fibrous cap thickness, indicating enhanced plaque stability.

Conclusions:

• MK2 inhibitors demonstrate efficacy in improving metabolic dysfunction and promoting atherosclerotic plaque stability in a preclinical model.
• These findings suggest that MK2 inhibitors hold therapeutic potential for managing T2D and its associated atherosclerotic vascular disease.
• Further clinical development of MK2 inhibitors may address the significant unmet need in T2D cardiovascular complications.