HINGEZ THERAPEUTICS INC — Department of Health and Human Services SBIR Phase I: NHLBI

Description

Abstract Heart disease remains the leading cause of death in the US accounting for nearly of all deaths annually A high cholesterol level is a well known risk factor for heart disease Although blood cholesterol low density lipoprotein LDL C can be lowered using a number of marketed drugs only of patients taking these drugs are achieving the desired goals Furthermore patients with homozygous familial hypercholesterolemia who have markedly elevated cholesterol levels respond poorly to current drug therapies and are at very high risk of premature cardiovascular disease These and other patients will benefit from an aggressive treatment of hypercholesterolemia A newly discovered protein proprotein convertase subtilisin kexin type PCSK plays an important role in cholesterol homeostasis by the expression of low density lipoprotein receptor LDLR on the cell membrane In fact gain and loss of function PCSK variations in human populations are associated with hyper or hypo cholesterolemia respectively Therefore PCSK inhibition has emerged as a promising option to treat hypercholesterolemia Indeed several strategies have been applied in the development of PCSK inhibitors including monoclonal antibodies mAbs and recently FDA has approved two anti PCSK mAbs However no orally administrable small molecules are approved Thus our approach is to develop a small molecule against PCSK Using our novel and disruptive HPC based platform we have characterized PCSK FGF AB crystal structure at the atomic level and generated numerous trajectories via molecule dynamic simulations We have already identified a few hits and tested in experimental assays We plan to use our in MD simulated trajectories for in silico lead optimization and generation of novel derivatives of hit molecules Subsequently we will validate the hits in cellular and functional assays by directly measuring LDLc uptake Narrative Atherosclerotic cardiovascular disease ASCVD is the leading cause of death and disability for men and women in the USA Hypercholesterolemia constitutes a major risk factor for the development of atherosclerosis and consequently ASCVD Despite the availability of statins and other lipid modified therapies LMTs many patients remain at high risk for ASCVD due to elevated low density lipoprotein LDL C Newly discovered protein proprotein convertase subtilisin like kexin type PCSK plays an important role in regulating circulating LDL cholesterol LDL C via LDL receptor LDLR Using our proprietary novel and disruptive HPC based discovery platform we have discovered small molecules that block PCSK LDLR interactions If successful these molecules will become a new class of drugs for the treatment of high cholesterol in patients whose cholesterol is not controlled with existing therapies