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

描述（由申请人提供）：真核细胞延伸因子2蛋白激酶（eEF 2K）是一种广泛表达的蛋白质，属于以“非典型”激酶结构域为特征的α激酶家族。我们最近的研究结果表明，抑制或基因失活的eEF 2K保护正常组织的化疗药物和电离辐射的细胞毒性作用。我们先前已经产生了eEF 2K缺陷动物，其没有不利的表型，但表现出对致死剂量的辐射和多柔比星诱导的细胞毒性的抗性增加。这种放射和化学抗性表型伴随着增殖组织中细胞凋亡水平的降低。我们假设eEF 2K的药理学抑制可以类似地保护组织免受化疗的有害副作用，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新型eEF 2K抑制剂。事实上，我们观察到一个候选的eEF 2K抑制剂LV 1053从阿霉素诱导的细胞死亡的大鼠成心肌细胞的显着保护。在I期可行性研究中，我们建议在基于细胞的系统中表征LV 1053的细胞保护特性，并在小鼠模型中确定其心脏保护特性。首先，我们将使用大鼠心肌母细胞系H9 C2在体外实验中建立LV 1053的有效浓度。其次，我们将在小鼠中进行药代动力学研究，以确定LV 1053在循环中的安全剂量和半衰期。第三，我们将使用多柔比星在小鼠中诱导心脏毒性，并将施用LV 1053以减少或消除与多柔比星相关的毒性。预计在完成I期研究后，我们将确定LV 1053在减轻化疗剂阿霉素的心脏毒性作用方面的疗效。对于减少由化疗剂和/或辐射引起的毒副作用的药物存在未满足的紧急医疗需求。因此，证明在体内药理学抑制eEF 2K以降低化疗药物毒性的可行性是非常重要的。如果第一阶段成功，下一步的第二阶段工作将包括使用各种动物模型进行更广泛的动物研究，以促进LV 1053快速过渡到人体临床试验。

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.