权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Small Molecule Antagonists of PF4 for the Treatment and Prevention of HIT

PF4 小分子拮抗剂治疗和预防 HIT

基本信息

批准号：
10016379
负责人：
Jay Edward Wrobel
金额：
$ 99.62万
依托单位：
FOX CHASE CHEMICAL DIVERSITY CENTER, INC
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-15 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016379
关键词：
Affect Ames Assay Amputation Animal Model Antibodies Anticoagulants Applications Grants Binding Binding Proteins Biological Assay Blood Blood Platelet Antagonists Blood Platelets Blood Vessels Blood coagulation Blood flow Canis familiaris Cardiac Catheterization Procedures Cardiopulmonary Bypass Cardiovascular system Cessation of life Chemicals Clinical Clinical Trials Coagulation Process Collaborations Complex Complication Cytochrome P450 Data Dialysis procedure Dose Equilibrium Evaluation Event Excision Foxes Functional disorder Funding Goals Grant Hemorrhage Heparin Hospitals Human In Vitro Individual Intravenous Isoenzymes Laboratories Lead Leukocytes Manuals Medical Modeling Mus New York Operative Surgical Procedures PF4 Gene Pathologic Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phase Plasma Plasma Proteins Platelet Activation Platelet Count measurement Platelet Inhibitors Preparation Prevention Preventive Intervention Process Prodrugs Property Proteins Rattus Risk Safety Scientist Small Business Innovation Research Grant Small Business Technology Transfer Research Sodium Chloride Solubility Testing Therapeutic Thrombin Thrombocytopenia Thrombosis Toxic effect Universities acute care analog base clinical development commercialization cytokine design dimer drug candidate drug discovery drug disposition experience heparin-induced thrombocytopenia immunoreaction improved in vitro Assay in vitro testing in vivo in vivo evaluation inhibitor/antagonist iterative design lead candidate lead optimization medical schools monomer mortality mouse model novel novel strategies patch clamp pre-clinical preclinical development prevent respiratory small molecule stability testing

项目摘要

We have discovered the first-ever inhibitors of PF4, a platelet protein central to the pathophysiology of heparin induced thrombocytopenia (HIT). Heparin is a naturally-occurring anticoagulant that prevents the formation of clots and extension of existing clots within the vasculature, and major medical applications of heparin include dialysis, cardiac catheterization, and cardiopulmonary bypass surgery. Heparin therapy is usually safe and effective; however, some patients (10,000-20,000 per year in the US) develop HIT as a serious complication caused by an immunological reaction that targets platelets leading to a low platelet count (thrombocytopenia). HIT increases the risk of blood clots forming within blood vessels and blocking the flow of blood (thrombosis), referred to as HITT when thrombosis occurs. HITT develops in approximately 1-3% of patients treated with heparin for 5-10 days. Affected individuals have a 20-50% risk of developing new thromboembolic events, a mortality rate ~20%, and an additional ~10% of patients require amputations or suffer other major pathological events. Current treatment for HIT relies on elimination of heparin exposure from patients with suspected HIT and administration of direct thrombin inhibitors, which carry a significant risk of bleeding. Despite the removal of heparin from these patients, they remain at significant risk for thrombosis and death. We have previously discovered a novel approach to the treatment of HIT via the destabilization of the functionally-active PF4 tetramers yielding inactive monomers and dimers. The tetrameric form of PF4 binds to heparin to form Ultralarge Complexes (ULC). Using the combined expertise of Fox Chase Chemical Diversity Center, Inc. in medicinal chemistry and drug discovery, the Sachais Laboratory at the New York Blood Center in HIT-based drug discovery approaches, and the McKenzie laboratory at Thomas Jefferson University in HIT mouse models, we have identified and characterized novel PF4 tetramerization inhibitors (PF4TIs) that disrupt PF4 tetramerization, ULC formation, and ameliorate HIT in an in vivo mouse model. In this grant proposal we plan to take our current lead FC-7259 or a related compound(s) as required into IND-enabling studies to support an IND application and eventual human clinical trials. During our first three aims in Yr 1 we will find alternative preclinical candidates, and backup compounds that could replace the current lead candidate if unforeseen liabilities are identified, via iterative synthesis and in vitro testing (lead optimization). The best compounds from lead optimization will undergo drug disposition evaluation (ADMET and PK), and the best among these will be evaluated in the HIT mouse model. Using this paradigm, we will choose the absolute best candidate for IND-enabling pre-clinical development activities in Yrs 2 and 3, including preparation of GMP drug substance and a 14 day repeat dose toxicity in rat and dog. By the end of this period of study, we expect to have PF4 tetramerization inhibitor preclinical drug candidates with suitable efficacy and safety properties to advance to an IND, ultimately leading to clinical development and commercialization as treatments for HITT.

我们首次发现了PF4的抑制剂，这是一种对肝素的病理生理起核心作用的血小板蛋白。诱发性血小板减少症(HIT)。肝素是一种天然的抗凝血剂，可防止肝素在血管内的血栓和现有血栓的延伸，肝素的主要医疗应用包括透析、心导管术和体外循环手术。肝素治疗通常是安全的有效；然而，一些患者(在美国每年10,000-20,000人)会发展为严重的并发症由针对血小板的免疫反应引起的，导致血小板数量减少(血小板减少症)。 HIT增加了血管内形成血栓并阻塞血液流动(血栓形成)的风险，血栓形成时称为HITT。大约1-3%的接受治疗的患者出现HITT 肝素治疗5-10天。受影响的个人有20%-50%的风险发展为新的血栓栓子事件，死亡率~20%，另有~10%的患者需要截肢或遭受其他重大疾病事件。目前对HIT的治疗依赖于消除疑似HIT患者的肝素暴露以及使用直接凝血酶抑制剂，这会带来很大的出血风险。尽管被移除了从这些患者的肝素，他们仍然处于血栓形成和死亡的重大风险。我们之前已经发现了一种通过功能活性PF4的失稳来治疗HIT的新方法四聚体，产生不活跃的单体和二聚体。四聚形式的PF4与肝素结合形成超大分子络合物(ULC)。利用Fox Chase化学多样性中心，Inc.在药物化学和药物发现，位于HIT的纽约血液中心的Sachais实验室药物发现的临近，以及托马斯·杰斐逊大学麦肯齐实验室的HIT MICE 模型，我们已经确定和表征了新型的PF4四聚抑制剂(PF4TIs)，它可以破坏PF4 在活体小鼠模型中的四聚化、ULC的形成和改善HIT。在这份赠款提案中，我们计划根据需要将我们目前的铅FC-7259或相关化合物(S)纳入IND使能研究以支持IND应用程序和最终的人体临床试验。在我们第一年的前三个目标中，我们将寻找替代的临床前候选药物，并在以下情况下寻找替代当前主要候选药物的备用化合物通过迭代合成和体外测试(引线优化)确定不可预见的风险。最好的从先导优化得到的化合物将接受药物处置评估(ADMET和PK)，最好的其中，将在点击小鼠模型中进行评估。使用这个范例，我们将选择绝对最好的第二年和第三年支持IND的临床前开发活动的候选人，包括GMP的准备对大鼠和狗的14d重复给药毒性。到这段时间的研究结束时，我们预计拥有具有合适疗效和安全性的PF4四聚抑制剂临床前候选药物发展到IND，最终导致HITT的临床开发和商业化。