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:
- 金额:$ 100万
- 依托单位:
- 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:
- 关键词:AffectAmes AssayAmputationAnimal ModelAntibodiesAnticoagulantsApplications GrantsBindingBinding ProteinsBiological AssayBloodBlood Platelet AntagonistsBlood PlateletsBlood VesselsBlood coagulationBlood flowCanis familiarisCardiac Catheterization ProceduresCardiopulmonary BypassCardiovascular systemCessation of lifeChemicalsClinicalClinical TrialsCoagulation ProcessCollaborationsComplexComplicationCytochrome P450DataDialysis procedureDoseEquilibriumEvaluationEventExcisionFoxesFunctional disorderFundingGoalsGrantHemorrhageHeparinHospitalsHumanIn VitroIndividualInterventionIntravenousIsoenzymesLaboratoriesLeadLeukocytesManualsMedicalModelingMusNew YorkOperative Surgical ProceduresPF4 GenePathologicPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologic SubstancePharmacologyPhasePhase 0 Clinical TrialPlasmaPlasma ProteinsPlatelet ActivationPlatelet Count measurementPlatelet InhibitorsPreparationPreventionProcessProdrugsPropertyProteinsRattusRiskSafetyScientistSmall Business Innovation Research GrantSmall Business Technology Transfer ResearchSodium ChlorideSolubilityTestingTherapeuticThrombinThrombocytopeniaThrombosisToxic effectUniversitiesacute careanalogbaseclinical developmentcommercializationcytokinedesigndimerdrug candidatedrug discoverydrug dispositionexperienceheparin-induced thrombocytopeniaimmunoreactionimprovedin vitro Assayin vitro testingin vivoin vivo evaluationinhibitor/antagonistiterative designlead candidatelead optimizationmedical schoolsmonomermortalitymouse modelnovelnovel strategiespatch clamppre-clinicalpreclinical developmentpreventrespiratorysmall moleculestability 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
项目成果
期刊论文数量(0)
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Jay Edward Wrobel其他文献
Jay Edward Wrobel的其他文献
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{{ 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:
$ 100万 - 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:
$ 100万 - 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:
$ 100万 - 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:
$ 100万 - 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:
$ 100万 - 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:
9751604 - 财政年份:2014
- 资助金额:
$ 100万 - 项目类别: