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：
10179443
负责人：
Jay Edward Wrobel
金额：
$ 100万
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10179443
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 Intervention 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 Phase 0 Clinical Trial Plasma Plasma Proteins Platelet Activation Platelet Count measurement Platelet Inhibitors Preparation Prevention 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.

我们发现了PF4的第一个抑制剂，PF4是肝素病理生理学中心的血小板蛋白诱导血小板减少症（HIT）。肝素是一种天然抗凝剂，可防止形成脉管系统内现有凝块的凝块和扩展，肝素的主要医学应用包括透析，心脏导管插入术和心肺旁路手术。肝素治疗通常是安全的，有效的;但是，有些患者（美国每年10,000-20,000）因严重的并发症而受到打击由靶向血小板的免疫反应引起的，导致血小板计数低（血小板减少症）。命中会增加血管内血凝块形成的风险，并阻止血液流动（血栓形成），发生血栓形成时称为HITT。 HITT在接受治疗的患者中大约有1-3％肝素5-10天。受影响的人有发展新的血栓栓塞事件的20-50％的风险死亡率约为20％，另外约10％的患者需要截肢或其他主要病理事件。当前的命中率治疗依赖于消除可疑命中患者的肝素暴露并给予直接凝血酶抑制剂，这些抑制剂具有出血的重大风险。尽管被删除这些患者的肝素，他们仍然有重大的血栓形成和死亡的风险。我们以前有发现了一种新颖的方法，可以通过功能活性PF4的不稳定来治疗命中率四聚体产生非活性单体和二聚体。 PF4的四聚体形式结合肝素形成超大配合物（ULC）。使用Fox Chase化学多样性中心，Inc。的联合专业知识药物化学和药物发现，基于纽约血液中心的Sachais实验室药物发现方法和托马斯·杰斐逊大学的麦肯齐实验室模型，我们已经确定并表征了新型的PF4四聚体抑制剂（PF4TIS），这些抑制剂破坏了PF4 在体内小鼠模型中，四聚体，ULC形成和改善命中。在这个赠款建议中我们计划将我们当前的铅FC-7259或相关化合物（S）纳入辅助研究支持IND应用和最终人类临床试验。在我们的前三个目标中，我们将查找替代的临床前候选者，以及可以替代当前主要候选人的备用化合物通过迭代合成和体外测试（铅优化）确定了不可预见的负债。最好的铅优化的化合物将接受药物处置评估（ADMET和PK），最好其中将在热门鼠标模型中评估。使用此范式，我们将选择绝对最好的在第2和3年中辅助临床前开发活动的候选人，包括GMP的准备大鼠和狗的药物和14天的重复剂量毒性。到这段研究结束时，我们期望具有适当疗效和安全性能的PF4四聚体抑制剂临床前药物候选者发展成为IND，最终导致临床发展和商业化，作为HITT的治疗方法。