Targeted inhibition of the SREBP-mediator interaction as a novel therapeutic
While most therapeutic approaches aimed at altering gene expression programs target upstream signaling pathways or nuclear translocation checkpoints, Scientists at the Wagner lab have provided mechanistic insights supporting an alternative approach, which is aimed at directly inhibiting the interaction of the SREBP transactivation domains (TADs) in the nucleus.
Scientists at the Wagner lab developed a dual-probe fluorescence polarization (FP)-based high-throughput assay to screen for small-molecule inhibitors that block SREBP directly. Two lead compounds were identified as efficient blockers of SREBP translation, while having negligible cytotoxic effects.
Current research is aimed at optimizing the leads, as well as characterizing additional small-molecule inhibitors of the SREBP-TAD interaction which will enable the development of therapeutics against aberrant cholesterol/lipid metabolism.
Intellectual Property Status: Patent(s) Pending
The World Health Organization identifies cardiovascular diseases (CVDs) as the primary cause of morbidity and mortality worldwide. Of the many risk factors for CVDs, conditions featuring metabolic dis-regulation, including hypertension, elevated blood glucose and/or lipid levels, diabetes, and obesity, are among the most common, with diabetes and obesity being epidemic in their own right. The Centers for Disease Control and Prevention (CDC) estimates there to be approximately 26 million diabetics in the United States alone, with a staggering 79 million additional individuals estimated to be pre-diabetic.
The Sterol Regulatory Element-Binding Protein (SREBP) family of transcription factors controls cholesterol and lipid homeostasis, adipocyte differentiation, and mediates lipogenic aspects of insulin-dependent gene expression. Obesity
due to imbalances in lipid metabolism and elevated blood sugar due to diabetes are both serious conditions to which SREBP family members are intimately linked, being strong risk factors for cardiovascular diseases, including hypertension and atherosclerosis. SREBPs have also been functionally linked to many metabolic diseases that are co-morbidities with CVDs. One evidence being, cholesterol-lowering statins which target HMG-CoA reductase- a key enzyme which is transcriptionally controlled by SREBP.