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

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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.