Development of a Small Molecule Inhibitor of Fortilin for Atherosclerosis Treatment and Prevention

开发用于治疗和预防动脉粥样硬化的 Fortilin 小分子抑制剂

基本信息

批准号：
10706870
负责人：
Ken Fujise
金额：
$ 15.3万
依托单位：
FORTISCIENCE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706870
关键词：
Acute Affect Affinity American Animals Apoptosis Arterial Fatty Streak Arteries Atherosclerosis Binding Biological Assay Biological Availability C57BL/6 Mouse Cardiovascular Diseases Cardiovascular system Cell Death Cell physiology Cells Cholesterol Clinical Trials Collaborations Data Development Dissociation Docking Dose Drug Kinetics Event Evolution Exhibits Foam Cells Future Goals Growth Half-Life Health In Vitro Inflammation Inflammatory Intervention LDL Cholesterol Lipoproteins Laboratories Lead Legal patent Life Lipids Liver Microsomes Macrophage Measures Metabolic Methods Modification Molecular Weight Mus Muscle Myocardial Infarction Non-Insulin-Dependent Diabetes Mellitus Oral Oral Administration Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phase Prevention Principal Investigator Proliferating Proteins Recurrence Research Research Contracts Risk Factors Risk Reduction Role Secondary Prevention Small Business Technology Transfer Research Stroke Structure Structure-Activity Relationship Symptoms TPT1 gene Testing Therapeutic Tissues Toxic effect Toxicokinetics United States National Institutes of Health Universities Washington Work appropriate dose computational chemistry cytokine cytotoxicity design diet and exercise drug-like compound experience first-in-human hypercholesterolemia improved in vivo in vivo Model inhibitor knock-down knockout gene lifestyle intervention medication safety mouse model nanomolar novel novel strategies novel therapeutics preclinical development preclinical study prevent programs screening side effect small molecule inhibitor smoking cessation therapeutic target timeline virtual

项目摘要

Project Summary Project Title: Development of a Small Molecule Inhibitor of Fortilin for Atherosclerosis Treatment and Prevention. Atherosclerosis affects more than 18 million Americans and is a major cause of cardiovascular diseases and acute cardiovascular events, such as heart attack and stroke. Current interventions include changes to diet and exercise, smoking cessation, and treatment with statins, but many patients struggle to adhere to lifestyle interventions and can experience significant side effects while taking statins. Although lipid lowering drugs have benefited patients with atherosclerosis, the idea that lipid lowering halts the progression of atherosclerosis is not valid because factors other than hypercholesterolemia have been shown to promote atherosclerosis. Therefore, there is a clear need for novel therapeutics that can directly inhibit plaque formation through a mechanism other than lipid lowering. Fortiscience, Inc. is developing an alternative therapeutic approach that inhibits fortilin, a key protein involved in atherosclerotic plaque formation. Fortilin protects macrophages against apoptosis in atherosclerotic intima, allowing them to proliferate and produce inflammatory cytokines. Strikingly, global knockdown of fortilin protects hypercholesterolemic mice against atherosclerosis without lowering cholesterol. Three small molecular weight compounds identified in preliminary work at the University of Washington have been shown to have activity in relevant in vitro and in vivo models, and these compounds have been used as the basis for designing and synthesizing 52 additional compounds with higher binding affinity through a medicinal chemistry approach. In this Phase I STTR project, to be conducted in collaboration with the University of Washington and the University of Notre Dame, 10 prioritized compounds will be evaluated using cell-based fortilin degradation and foam cell formation assays to assess activity (measuring the EC50) and cell death assays to determine cytotoxicity (LC50). Based on an analysis of the structure–activity relationship for these compounds, computational virtual docking assays will be performed to design and produce 3-5 new compounds with improved fortilin binding affinity. The binding affinity, activity, toxicity, and stability of these compounds will then be measured, and the data will be used to select a lead compound with a single-nanomolar dissociation constant, a lower EC50 value than the previous best-performing compound, and low clearance in liver microsome assays (CLint below 15 mL min-1kg-1). Further, pharmacokinetic and toxicity profiles will be determined for the lead compound in a 15-day oral dose range finding study in C57BL/6 mice. Finally, the anti-atherosclerotic activity of the lead compound will be determined in the aortae of hypercholesterolemic mice following 12 weeks of oral administration, with the goal of achieving a 50% reduction in atherosclerosis. This work is designed to provide the necessary proof-of-concept data to support further pre-clinical studies in Phase II and a future first-in-human clinical trial to establish the safety of the drug.

项目概要项目名称：开发用于动脉粥样硬化治疗和治疗的 Fortilin 小分子抑制剂预防动脉粥样硬化影响超过 1800 万美国人，是心血管疾病的主要原因。目前的干预措施包括心脏病和中风等疾病和急性心血管事件。改变饮食和运动、戒烟以及使用他汀类药物治疗，但许多患者都在努力坚持生活方式干预，服用他汀类药物时可能会出现明显的副作用。降脂药物使动脉粥样硬化患者受益，降脂药物可以阻止动脉粥样硬化的进展动脉粥样硬化是无效的，因为高胆固醇血症以外的因素已被证明可以促进因此，显然需要能够直接抑制斑块形成的新疗法。 Fortiscience, Inc. 正在开发一种替代疗法。抑制 Fortilin 的方法，Fortilin 是参与动脉粥样硬化斑块形成的关键蛋白。巨噬细胞对抗动脉粥样硬化内膜中的细胞凋亡，使其增殖并产生炎症引人注目的是，福替林的整体敲低可保护高胆固醇血症小鼠免受动脉粥样硬化的影响。初步工作中鉴定出三种小分子量化合物。华盛顿大学已被证明在相关的体外和体内模型中具有活性，并且这些化合物已被用作设计和合成另外 52 种具有更高性能的化合物的基础在此第一阶段 STTR 项目中，通过药物化学方法进行结合亲和力。与华盛顿大学和圣母大学合作，将开发 10 种优先化合物使用基于细胞的 fortilin 降解和泡沫细胞形成测定来评估活性（测量 EC50）和细胞死亡测定法以确定细胞毒性（LC50）基于结构-活性分析。对于这些化合物的关系，将进行计算虚拟对接分析来设计和产生 3-5 种具有改进的福替林结合亲和力的新化合物然后将测量这些化合物的稳定性，并且该数据将用于选择具有以下性质的先导化合物：单纳摩尔解离常数，比之前性能最佳的化合物更低的 EC50 值，以及肝微粒体测定中清除率低（CLint 低于 15 mL min-1kg-1）此外，药代动力学和毒性。将在 C57BL/6 小鼠的 15 天口服剂量范围探索研究中确定先导化合物的概况。最后，将在主动脉中测定先导化合物的抗动脉粥样硬化活性高胆固醇血症小鼠口服 12 周后，目标是达到 50% 这项工作旨在提供必要的概念验证数据来支持。进一步的二期临床前研究和未来的首次人体临床试验以确定该药物的安全性。