Selective inhibitors of ubiquitin E3 ligase to treat high cholesterol

DESCRIPTION provided by applicant Hypercholesterolemia is a major risk factor in cardiovascular diseases it is estimated that andgt million individuals in the U S or one sixth of the adult population have high total cholesterol and thus twice the risk of heart disease compared to those with optimal cholesterol levels While statins are widely prescribed for cholesterol lowering their serious side effect profile makes the risk benefit consideration an important factor in a physicianandapos s decision to prescribe them In addition single agent statins are susceptible to the development of resistance in patients Thus a need exists for new drugs that differ from statins in their therapeutic mechanisms such drugs used singly have the potential to cause fewer side effects than statins but more important they could be used in combination with existing agents to prevent facile development of resistance Nearly all cholesterol lowering drugs are directed at increasing the activity of the LDL Receptor LDLR which is primarily responsible for clearing cholesterol from the serum this physiological endpoint can be achieved through a number of biochemically distinct mechanisms Progenraandapos s Phase I therapeutic hypothesis proposed to increase LDLR activity by maximizing its population utilizing the ubiquitin proteasome pathway a novel area for drug discovery The posited therapeutic target Idol is a RING finger E ubiquitin ligase that conjugates ubiquitin to the LDLR on its cytoplasmic domain resulting in its subsequent degradation inhibitors of this ligase would effectively increase the average levels of LDLR The pharmacologic outcome would be a reduction is the serum cholesterol level and LDLR up regulation is an established approach for cholesterol lowering In fact a recent study demonstrated increased LDLR in mouse Idol knockout models An Idol inhibitor would accomplish this therapeutic step by a completely novel mechanism In addition a selective inhibitor of Idol would be likely to produce minimal side effects In Phase I therefore a high throughput screening assay for inhibitors of Idol was established and validated and a screen was conducted on a set of small molecules Several suitable hits were obtained in this screen In Phase II it is proposed to perform chemical optimization on hits validated for potency and selectivity and initiate preclinical development of selected optimized analogues using biochemical and cell based secondary assays and animal models of drug metabolism pharmacokinetic properties and LDL clearance efficacy The purpose of Phase II is to identify potent and selective compounds with efficacy as cholesterol lowering therapeutic agents PUBLIC HEALTH RELEVANCE High cholesterol affects millions of people worldwide who accordingly face increased risk of developing heart disease The current drug of choice for lowering cholesterol is the family of statins which work by increasing the binding of andquot badandquot cholesterol to its receptors and thereby promote clearance of cholesterol from the bloodstream Although widely prescribed statins are associated with adverse reactions in many patients Progenra is studying a promising new target for cholesterol lowering drug discovery an enzyme known as Idol and proposes to identify and develop Idol inhibitors which are expected to increase LDLR levels by preventing degradation of the receptor with minimal side effects as improved novel high cholesterol treatment