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

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)。利用福克斯大通化学多样性中心,公司的综合专业知识。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。使用这个范式,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。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Jay Edward Wrobel其他文献

Jay Edward Wrobel的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Jay Edward Wrobel', 18)}}的其他基金

Development of FosA Inhibitors to Potentiate Fosfomycin Activity in Gram-Negative Pathogens
开发 FosA 抑制剂以增强磷霉素对革兰氏阴性病原体的活性
  • 批准号:
    10545935
  • 财政年份:
    2022
  • 资助金额:
    $ 99.99万
  • 项目类别:
Development of FosA Inhibitors to Potentiate Fosfomycin Activity in Gram-Negative Pathogens
开发 FosA 抑制剂以增强磷霉素对革兰氏阴性病原体的活性
  • 批准号:
    10684118
  • 财政年份:
    2022
  • 资助金额:
    $ 99.99万
  • 项目类别:
INHIBITORS OF THE PHD2 ZINC FINGER TO TREAT ANEMIA
PHD2 锌指抑制剂治疗贫血
  • 批准号:
    9345190
  • 财政年份:
    2017
  • 资助金额:
    $ 99.99万
  • 项目类别:
Pregnane X Receptor (PXR) Antagonists for Non-Alcoholic Fatty Liver Disease
孕烷 X 受体 (PXR) 拮抗剂治疗非酒精性脂肪肝
  • 批准号:
    8905004
  • 财政年份:
    2015
  • 资助金额:
    $ 99.99万
  • 项目类别:
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:
    10016379
  • 财政年份:
    2014
  • 资助金额:
    $ 99.99万
  • 项目类别:
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:
    10179443
  • 财政年份:
    2014
  • 资助金额:
    $ 99.99万
  • 项目类别:

相似海外基金

RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
  • 批准号:
    2327346
  • 财政年份:
    2024
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Standard Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
  • 批准号:
    2312555
  • 财政年份:
    2024
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Standard Grant
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
  • 批准号:
    BB/Z514391/1
  • 财政年份:
    2024
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Training Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
  • 批准号:
    ES/Z502595/1
  • 财政年份:
    2024
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Fellowship
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
  • 批准号:
    ES/Z000149/1
  • 财政年份:
    2024
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Research Grant
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
  • 批准号:
    23K24936
  • 财政年份:
    2024
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
  • 批准号:
    2901648
  • 财政年份:
    2024
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Studentship
ERI: Developing a Trust-supporting Design Framework with Affect for Human-AI Collaboration
ERI:开发一个支持信任的设计框架,影响人类与人工智能的协作
  • 批准号:
    2301846
  • 财政年份:
    2023
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Standard Grant
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
  • 批准号:
    488039
  • 财政年份:
    2023
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Operating Grants
How motor impairments due to neurodegenerative diseases affect masticatory movements
神经退行性疾病引起的运动障碍如何影响咀嚼运动
  • 批准号:
    23K16076
  • 财政年份:
    2023
  • 资助金额:
    $ 99.99万
  • 项目类别:
    Grant-in-Aid for Early-Career Scientists
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了