Use of EF2K Inhibitors to Reduce Toxicity to Normal Tissues in Chemotherapy

使用 EF2K 抑制剂降低化疗中对正常组织的毒性

基本信息

批准号：
8782369
负责人：
ALEXEY G. RYAZANOV
金额：
$ 22.2万
依托单位：
LONGEVICA PHARMACEUTICALS, 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：
2014-08-01 至 2015-07-01
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8782369
关键词：
Adverse effects Animal Model Animals Antineoplastic Agents Apoptosis Blood Circulation Cardiotoxicity Cell Death Cell Line Cells Characteristics Chemoprotection Chemoprotective Agent Clinical Trials Data Dose Dose-Limiting Doxorubicin Drug Kinetics Equilibrium Family Feasibility Studies Genetic Half-Life Histopathology Human In Vitro Incel Ionizing radiation Medical Modeling Mus Normal tissue morphology Patients Peptide Elongation Factor 2 Pharmaceutical Preparations Phase Phenotype Phosphotransferases Proliferating Property Protein Kinase Protein Kinase Inhibitors Proteins Quality of life Radiation Radio Radioprotection Rattus Regimen Resistance Series System Testing Tissues Toxic effect Toxicity due to chemotherapy base calmodulin-dependent protein kinase III cancer therapy chemotherapeutic agent chemotherapy cytotoxic cytotoxicity dosage improved in vivo inhibitor/antagonist mouse model novel phase 1 study protective effect protein kinase inhibitor public health relevance research study screening

项目摘要

DESCRIPTION (provided by applicant): Eukaryotic elongation factor 2 protein kinase (eEF2K) is a ubiquitously expressed protein that belongs to a family of alpha kinases characterized by an "atypical" kinase domain. Our recent findings demonstrate that inhibition or genetic inactivation of eEF2K protects normal tissues from cytotoxic effects of chemotherapeutic agents and ionizing radiation. We have previously generated eEF2K-deficient animals that that have no adverse phenotypes but demonstrate increased resistance to both lethal doses of radiation and doxorubicin- induced cytotoxicity. This radio- and chemoresistant phenotype is accompanied by decreased levels of apoptosis in proliferating tissues. We hypothesized that pharmacological inhibition of eEF2K may similarly protect the tissues from the harmful side effects of chemotherapy and tested our own series of novel inhibitors of eEF2K in cell-based model of cardiotoxicity. Indeed, we observed a marked protection of rat cardiomyoblasts from doxorubicin-induced cell death by a candidate eEF2K inhibitor LV1053. In Phase I feasibility study, we propose to characterize cytoprotective properties of LV1053 in cell-based system and to determine its cardioprotective characteristics in mouse models. First, we will establish effective concentrations of LV1053 in the in vitro experiments using rat cardiomyblast cell line H9C2. Second, we will carry out pharmacokinetic studies in mice to establish safe dosage and half-life of LV1053 in the circulation. Third, we will use doxorubicin to induce cardiotoxicity in mice and will administer LV1053 to reduce or eliminate toxicity associated with the doxorubicin. It is anticipated that upon completion of Phase I study we will establish efficacy of LV1053 in mitigation of cardiotoxic effects of chemotherapeutic agent doxorubicin. There is an unmet urgent medical need for the drugs that reduce toxic side effects caused by chemotherapeutic agents and/or radiation. Therefore, demonstration of feasibility of pharmacological inhibition of eEF2K in vivo in order to reduce the toxicity of chemotherapy drugs is very important. If Phase I is successful, the next step Phase II effort will include broader animal studies using various animal models to facilitate rapid transition of LV1053 into human clinical trials.

描述（由申请人提供）：真核伸长因子2蛋白激酶（EEF2K）是一种普遍表达的蛋白质，属于以“异型”激酶结构域为特征的α激酶家族。我们最近的发现表明，EEF2K的抑制或遗传失活可保护正常组织免受化学治疗剂和电离辐射的细胞毒性作用。我们以前已经产生了没有不良表型的EEF2K不足的动物，但表现出对致命剂量的辐射和阿霉素诱导的细胞毒性的抗性。这种放射性和化学抗性表型伴随着增殖组织中凋亡水平降低。我们假设对EEF2K的药理抑制可能会类似地保护组织免受化学疗法的有害副作用，并在基于细胞的心脏毒性模型中测试了我们自己的一系列EEF2K新型EEF2K抑制剂。确实，我们观察到了大鼠心脏肌细胞对阿霉素诱导的细胞死亡的明显保护，候选EEF2K抑制剂LV1053。在第一阶段的可行性研究中，我们建议表征LV1053在基于细胞系统中的细胞保护特性，并确定其在小鼠模型中的心脏保护特性。首先，我们将使用大鼠心脏母细胞系H9C2在体外实验中建立LV1053的有效浓度。其次，我们将在小鼠中进行药代动力学研究，以在循环中建立LV1053的安全剂量和半衰期。第三，我们将使用阿霉素在小鼠中诱导心脏毒性，并施用LV1053来降低或消除与阿霉素相关的毒性。可以预计，在完成I期研究后，我们将确定LV1053在减轻化学治疗剂阿霉素的心脏毒性作用方面的功效。对减少化学治疗剂和/或辐射引起的毒性副作用的药物的迫切需要医疗需求。因此，为了降低化学疗法药物的毒性，表现出对EEF2K的药理抑制的可行性非常重要。如果I期成功，下一步的II阶段将包括使用各种动物模型的更广泛的动物研究，以促进LV1053快速过渡到人类临床试验。