Small Molecule Inhibitors of PCSK9-Phase II

PCSK9-Phase II 的小分子抑制剂

基本信息

批准号：
9762193
负责人：
Peter U Feig
金额：
$ 90.92万
依托单位：
HINGEZ THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-19 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9762193
关键词：
ABCB1 gene Accounting Affinity Age Area Atherosclerosis Back Binding Biological Assay Blood Caco-2 Cells Cardiovascular Diseases Catalytic Domain Cause of Death Cell membrane Cell surface Cellular Assay Cessation of life Chemicals Cholesterol Cholesterol Homeostasis Clinical Computer Simulation Crystallization Crystallography Cytochromes Data Development Dimensions Disease Docking Dose Drug Kinetics Epidermal Growth Factor Familial Hypercholesterolemia First Name Free Energy Generations Goals Heart Diseases Hepatocyte High Performance Computing Homology Modeling Human In Vitro Injections Investigation LDL Cholesterol Lipoproteins Lead Libraries Lipids Low Density Lipoprotein Receptor Low-Density Lipoproteins Measurement Metabolic Molecular Molecular Conformation Monoclonal Antibodies Monoclonal Antibody Therapy Oral Patients Permeability Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Plant Roots Play Population Property Proprotein Convertases Proteins Randomized Controlled Trials Resolution Risk Factors Role Serum Solubility Structure Subtilisin Like Proprotein Convertases Subtilisins Surface Plasmon Resonance Techniques Testing Toxic effect Transgenic Mice Transgenic Organisms Variant Woman analog animal efficacy atherosclerosis risk base cholesterol control design disability drug discovery drug market flexibility gain of function mutation high risk hypercholesterolemia in vitro Assay in vivo inhibitor/antagonist lead optimization loss of function men mouse model mutant novel novel drug class novel therapeutics premature primary endpoint protein protein interaction receptor receptor density receptor expression response restoration scaffold side effect simulation small molecule small molecule inhibitor therapy duration uptake

项目摘要

Abstract Heart disease remains the leading cause of death in the US, accounting for nearly 40% 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 38% 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 9 (PCSK9) 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 PCSK9 variations in human populations are associated with hyper- or hypo cholesterolemia respectively. Therefore, PCSK9 inhibition has emerged as a promising option to treat hypercholesterolemia. Indeed, several strategies have been applied in the development of PCSK9 inhibitors including monoclonal antibodies (mAbs), and recently FDA has approved two anti-PCSK9 mAbs. However, no orally administrable small molecules are approved. Thus, our approach is to develop a small molecule PCSK9 inhibitor. Using our novel and disruptive HPC-based platform, we have characterized PCSK9 structure at the atomic level and generated numerous trajectories via molecule dynamic simulations. We have validated several ‘hits’ molecules in experimental assays. We plan to develop the hits and generate lead molecules of diverse scaffolds using in vivo cellular assays and transgenic efficacy animal.

抽象的心脏病仍然是美国的首要死因，每年占所有死亡人数的近 40%。高胆固醇水平是众所周知的心脏病危险因素。许多市售药物可以降低脂蛋白（LDL-C），但只有 38% 的患者服用这些药物此外，患有纯合子家族性高胆固醇血症的患者也正在实现预期目标。胆固醇水平明显升高，对当前药物治疗反应不佳，并且有很高的风险这些和其他患者将受益于积极的治疗。一种新发现的蛋白质-前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型（PCSK9）发挥作用。低密度脂蛋白受体（LDLR）的表达在胆固醇稳态中发挥重要作用事实上，人类群体中 PCSK9 功能的获得和丧失变异与细胞膜相关。因此，PCSK9 抑制已成为治疗高胆固醇血症或低胆固醇血症的一个有前途的选择。事实上，在 PCSK9 抑制剂的开发中已经应用了多种策略。包括单克隆抗体（mAb），最近 FDA 批准了两种抗 PCSK9 mAb，但尚未批准。口服小分子获得批准，因此，我们的方法是开发小分子 PCSK9。使用我们新颖且具有颠覆性的基于 HPC 的平台，我们表征了 PCSK9 的结构。原子水平并通过分子动力学模拟生成了许多轨迹。我们计划在实验分析中开发“命中”分子并生成多种先导分子。使用体内细胞测定和转基因功效动物的支架。