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

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