PCSK9-LDLR inhibitors from fragment-based design

基于片段设计的 PCSK9-LDLR 抑制剂

• 批准号: 8592507
• 负责人: John Laurence Kulp III
• 金额: $ 21.67万
• 依托单位: BIOLEAP, LLC
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8592507
• 关键词: Address; Affinity; Algorithms; Antibodies; Binding; Binding Proteins; Biochemical; Biological Assay; Biological Availability; Cells; Charge; Chemicals; Chemistry; Cholesterol; Clinical; Clinical Research; Clinical Trials; Coronary heart disease; Data; Dehydration; Development; Dihydrofolate Reductase; Dose; Drosophila pros protein; Drug Kinetics; Evaluation; Fluorescence Resonance Energy Transfer; Future; Goals; Hepatocyte; Hot Spot; Human; LDL Cholesterol Lipoproteins; Libraries; Licensing; Ligands; Link; Lipoprotein Receptor; Maps; Methodology; Methods; Outcome; Patients; Peptides; Performance; Pharmacologic Substance; Phase; Phase II Clinical Trials; Process; Property; Proteins; Quantum Mechanics; Renin; Reporting; Research; Running; Simulate; Site; Solubility; Solvents; Stress; Structure; Structure-Activity Relationship; Subtilisins; Surface Plasmon Resonance; Techniques; Test Result; Testing; Therapeutic; Triage; Water; base; cost; design; design and construction; drug discovery; fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether; functional group; high throughput screening; hypercholesterolemia; improved; inhibitor/antagonist; insight; kexin; meetings; molecular dynamics; novel; physical property; primary outcome; programs; public health relevance; quantum; receptor; receptor binding; simulation; small molecule; success; uptake

DESCRIPTION: Recent phase II clinical studies demonstrate that an antibody targeting proportion convertase subtilisin/kexin type 9 (PCSK9)-a target for the treatment of hypercholesterolemia and coronary heart disease-successfully and safely decreases amounts of low-density lipoprotein-cholesterol (LDL) in patients with hypercholesterolaemia undertaking statin treatment.1,2 However, to date, there are no reports of small molecules or peptides achieving the same effect. This application offers a mature fragment-based design methodology to create novel small molecule PCSK9 inhibitors that achieve a targeted activity in surface plasmon resonance direct and competition assays as well as in a functional assay, LDL uptake in hepatocyte cells. Such an alternative approach to this problem is compelling because high-throughput screening campaigns at large pharmaceutical companies have generally not yielded progressable hits for PCSK9. Using our recently described hot-spot mapping technique,3,6 we found sites at the low-density lipoprotein-cholesterol receptor (LDLR)/PCSK9 interface that are sites of high interaction energy and appear druggable. Our primary deliverable for the proposed research is to improve physical properties and develop SAR around our initial hits that show functional cell-based activity. The primary hits resulted from testing fewer than 50 novel compounds (one, two and three fragment builds). The small molecule ligands were specifically designed to implement a hypothesis that quantum resonance (partially covalent binding) can provide enhanced affinity to overcome the dehydration costs of the convex, solvent-exposed PCSK9/LDLR interface. Such compounds achieving success in clinical trials would show great promise as a therapeutic to lower cholesterol and treat coronary heart disease in humans.

产品说明：最近的II期临床研究表明，靶向比例转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）的抗体-高胆固醇血症和冠心病的治疗靶点-成功且安全地降低了接受他汀类药物治疗的高胆固醇血症患者的低密度脂蛋白胆固醇（LDL）量。1，2然而，迄今为止，没有报道小分子或肽达到相同的效果。该申请提供了一种成熟的基于片段的设计方法，以创建新型小分子PCSK 9抑制剂，该抑制剂在表面等离子体共振直接和竞争测定以及功能测定中实现靶向活性，即肝细胞中的LDL摄取。这种解决这个问题的替代方法是引人注目的，因为大型制药公司的高通量筛选活动通常不会产生对PCSK 9的可进展的命中。使用我们最近描述的热点定位技术，3，6我们发现低密度脂蛋白胆固醇受体（LDLR）/PCSK 9界面的位点是高相互作用能的位点，并且似乎是可药用的。我们提出的研究的主要成果是改善物理性质，并围绕我们的初步命中，显示功能性细胞为基础的活动，开发SAR。主要命中来自测试不到50种新化合物（一种、两种和三种片段构建）。小分子配体被专门设计用于实现量子共振（部分共价结合）可以提供增强的亲和力以克服凸的、溶剂暴露的PCSK 9/LDLR界面的脱水成本的假设。这些化合物在临床试验中取得成功，将显示出作为降低胆固醇和治疗人类冠心病的治疗剂的巨大前景。