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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.

我们已经发现了PF4的第一个抑制剂，PF4是肝素病理生理的核心血小板蛋白