Identification of new chemical entities targeting APE1 for the prevention of chemotherapy-induced peripheral neuropathy (CIPN)

Abstract

Chemotherapy-induced peripheral neuropathy (CIPN) is a potentially debilitating side effect of a number of chemotherapeutic agents that does not have any FDA-approved interventions or prevention strategies. Although the cellular mechanisms mediating CIPN remain to be determined, several lines of evidence support the notion that DNA damage may be a causative factor in neuropathy induced by a number of cancer therapies. Therapies including platinum agents and ionizing radiation cause DNA damage in sensory neurons and augmenting key steps in the base excision repair (BER) pathway reverses this damage. Neuronal protection is provided by overexpressing APE1 as well as using a first generation targeted APE1 small molecule E3330 (also called APX3330). Accordingly, we determined whether novel second-generation APE1 targeted molecules would be protective against neurotoxicity-induced by cisplatin or oxaliplatin while not diminishing the anti-tumor effect of the platins. We determined using our ex vivo model of sensory neurons in culture measuring various endpoints of neurotoxicity that APX2009 is an effective small molecule that is neuroprotective against cisplatin and oxaliplatin-induced toxicity of sensory neurons. APX2009 also demonstrated a strong tumor cell killing effect in tumor cells. Additionally, the enhanced tumor cell killing was further shown in a more robust 3D pancreatic tumor model. Together, these data suggest that APX2009 is effective in preventing or reversing platinum-induced CIPN, while not affecting the anti-cancer activity of platins.