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

• 批准号: 9751604
• 负责人: Jay Edward Wrobel
• 金额: $ 99.99万
• 依托单位: FOX CHASE CHEMICAL DIVERSITY CENTER, INC
• 依托单位国家: 美国
• 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/9751604
• 关键词: Acute; 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; Caring; 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; Pathologic; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Plasma; Plasma Proteins; Platelet Activation; Platelet Count measurement; Platelet Factor 4; 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; 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

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PF 4的抑制剂，PF 4是一种血小板蛋白，对肝素的病理生理学起着重要作用 血小板减少症（HIT）。肝素是一种天然的抗凝剂，可防止 血栓和血管系统内现有血栓的扩展，肝素的主要医疗应用包括 透析、心导管插入术和心肺旁路手术。肝素治疗通常是安全的， 有效;然而，一些患者（美国每年10，000 - 20，000例）发生HIT作为严重并发症 由靶向血小板的免疫反应引起，导致血小板计数降低（血小板减少症）。 HIT增加了血管内形成血凝块并阻塞血液流动（血栓形成）的风险， 当血栓形成发生时称为HITT。HITT发生在约1-3%的接受以下治疗的患者中： 肝素5-10天。受影响的个体有20-50%的风险发生新的血栓栓塞事件， 死亡率约为20%，另外约10%的患者需要截肢或患有其他重大病理性疾病。 事件目前对HIT的治疗依赖于消除疑似HIT患者的肝素暴露 以及直接凝血酶抑制剂的施用，其具有显著的出血风险。尽管移除 尽管这些患者体内肝素的含量很低，但他们仍有血栓形成和死亡的重大风险。我们先前已经 发现了一种通过功能活性PF 4的去稳定化来治疗HIT的新方法 产生无活性单体和二聚体的四聚体。PF 4的四聚体形式与肝素结合形成 超大型络合物（ULC）。利用Fox Chase Chemical Diversity Center，Inc.的综合专业知识在 药物化学和药物发现，萨查斯实验室在纽约血液中心在HIT的基础上， 药物发现方法，以及托马斯杰斐逊大学的McKenzie实验室在HIT小鼠 模型，我们已经确定并表征了新的PF 4四聚体抑制剂（PF 4 TIs），破坏PF 4 四聚化、ULC形成和改善体内小鼠模型中HIT。在这份赠款提案中，我们 计划根据需要将我们目前的先导化合物FC-7259或相关化合物纳入IND使能研究 以支持IND申请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，以及可以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（先导物优化），识别不可预见的责任。最好的 来自先导化合物优化的化合物将进行药物处置评价（ADMET和PK）， 其中将在HIT小鼠模型中进行评价。使用这个范例，我们将选择绝对最好的 第2年和第3年IND启动临床前开发活动的候选人，包括GMP的编制 大鼠和犬中的原料药和14天重复给药毒性。在本研究结束时，我们预计 获得具有合适功效和安全性质的PF 4四聚化抑制剂临床前药物候选物， 推进到IND，最终导致临床开发和商业化作为HITT的治疗。