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This chapter focuses on APE1 (AP endonuclease or redox factor 1; APE1/Ref-1, Ref-1 or APE1), which has multiple functions in DNA repair, transcriptional regulation, and RNA processing. APE1 is the endonuclease in base excision repair and also a major redox signaling factor for several important transcription factors that have been implicated in many human pathologies. Through redox signaling, APE1 enables transcription factors such as p53, STAT3, NFκB, HIF1α and others, to activate the transcription of their downstream targets. These diverse functions translate into roles in diverse diseases such as cancer, cancer-induced neuropathy and cachexia, ocular disease, and inflammatory bowel disease. APX3330, an APE1 redox inhibitor successfully completed a Phase I trial for safety and toxicity and has robust activity in preclinical trials using many different models. Bioinformatic analyses of cells with altered APE1 levels have expanded our knowledge of pathways that APE1 influences, confirming its role in others such as metabolism, cellular stress response, and oxidative stress. Future directions include additional clinical trials with APX3330 and development of second-generation analogs for use in ocular and potentially other indications. Additionally, profiling patient samples for signatures that predict response to APE1-targeted therapeutics will become more of a reality. |
