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

Description

Abstract Heart disease remains the leading cause of death in the USaccounting for nearlyof all deaths annuallyA high cholesterol level is a well known risk factor for heart diseaseAlthough blood cholesterollow density lipoproteinLDL Ccan be lowered using a number of marketed drugsonlyof patients taking these drugs are achieving the desired goalsFurthermorepatients with homozygous familial hypercholesterolemiawho have markedly elevated cholesterol levelsrespond poorly to current drug therapiesand are at very high risk of premature cardiovascular diseaseThese and other patients will benefit from an aggressive treatment of hypercholesterolemiaA newly discovered proteinproprotein convertase subtilisin kexin typePCSKplays an important role in cholesterol homeostasis by the expression of low density lipoprotein receptorLDLRon the cell membraneIn factgainand loss of function PCSKvariations in human populations are associated with hyperor hypo cholesterolemia respectivelyThereforePCSKinhibition has emerged as a promising option to treat hypercholesterolemiaIndeedseveral strategies have been applied in the development of PCSKinhibitors including monoclonal antibodiesmAbsand recently FDA has approved two anti PCSKmAbsHoweverno orally administrable small molecules are approvedThusour approach is to develop a small molecule PCSKinhibitorUsing our novel and disruptive HPC based platformwe have characterized PCSKstructure at the atomic level and generated numerous trajectories via molecule dynamic simulationsWe have validated severalhitsmolecules in experimental assaysWe plan to develop the hits and generate lead molecules of diverse scaffolds using in vivo cellular assays and transgenic efficacy animal Narrative Atherosclerotic cardiovascular diseaseASCVDis the leading cause of death and disability for men and women in the USAHypercholesterolemia constitutes a major risk factor for the development of atherosclerosis and consequently ASCVDDespite the availability of statins and other lipid modified therapiesLMTsmany patients remain at high risk for ASCVD due to elevated low density lipoproteinLDL CNewly discovered proteinproprotein convertase subtilisin like kexin typePCSKplays an important role in regulating circulating LDLcholesterolLDL Cvia LDL receptorLDLRUsing our proprietary novel and disruptive HPC based discovery platformwe have discovered small molecules that block PCSKLDLR interactionsIf successfulthese molecules will become a new class of drugs for the treatment of high cholesterol in patients whose cholesterol is not controlled with existing therapies