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

描述（由申请人提供）：真核延伸因子2蛋白激酶（eEF2K）是一种普遍表达的蛋白，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，eEF2K的抑制或基因失活可以保护正常组织免受化疗药物和电离辐射的细胞毒性作用。我们之前已经产生了eef2k缺陷的动物，这些动物没有不良表型，但对致死剂量的辐射和阿霉素诱导的细胞毒性均表现出更高的耐药性。这种放射和化疗耐药表型伴随着增殖组织中细胞凋亡水平的降低。我们假设eEF2K的药理学抑制可能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eEF2K抑制剂。事实上，我们观察到候选eEF2K抑制剂LV1053对阿霉素诱导的大鼠心肌细胞死亡有明显的保护作用。在I期可行性研究中，我们建议在细胞为基础的系统中表征LV1053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，我们将利用大鼠心肌细胞H9C2进行体外实验，建立LV1053有效浓度。其次，我们将在小鼠体内进行药代动力学研究，建立LV1053在血液循环中的安全剂量和半衰期。第三，我们将使用阿霉素诱导小鼠心脏毒性，并给予LV1053以减少或消除与阿霉素相关的毒性。预计在I期研究完成后，我们将确定LV1053在减轻化疗药物阿霉素心脏毒性作用方面的疗效。对减少化疗药物和/或放疗引起的毒副作用的药物的迫切医疗需求尚未得到满足。因此，在体内证明药理抑制eEF2K的可行性，以降低化疗药物的毒性是非常重要的。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的更广泛的动物研究，以促进LV1053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.