Apurinic/apyrimidinic DNA repair endonuclease-1 (APE-1) is an important DNA excision repair enzyme, which also has a redox regulatory function known as Redox Factor-1 (Ref-1) and activates many nuclear transcription factors;hence the abbreviation APE/Ref-1. Taking APE/Ref-1 as an attractive druggable target, many efforts have been devoted in recent years to develop potent inhibitors for the treatment of human malignancies;but to the best of our knowledge, only limited success has been reported. This proposal centers on the development of novel redox inhibitors of APE/Ref-1 utilizing structure- based approaches with chemical optimization of our lead compounds, given the fact that the redox function of APE/Ref-1 plays a critical role in reactive oxygen species (ROS)-associated inflammatory states, carcinogenesis and malignant progression. Candidate compounds identified in our screening will be advanced to further bio-evaluation both in vitro and in vivo. W expect to develop 1-2 candidate APE/Ref-1 redox inhibitors that exhibit promising preclinical activity and ready for translation to clinical treatment and possibly therapeutic prevention trials within the next 5 years. In order to achieve this scientific and translational goal, a career development grant will provide me with the necessary funding, mentorship, and experience to become an independent clinician scientist working in an environment that is highly conductive to promoting and sustaining success of young investigators. This career development grant will provide me the opportunity for relevant comprehensive training and development of the requisite expertise to assemble and lead a multi-expertise team in drug development.
To expand my capabilities as a clinical pharmacist, the proposed training and mentoring specifically focusing on clinical pharmacology and drug development will prepare me well for a career as an independent clinician investigator, with a focus on pharmaceutical drug discovery. In the proposed study, we will utilize structure-based approaches to guide the synthesis of novel small molecules targeting APE/Ref-1 and its redox function. Eventually I will translate our discoveries into breakthrough therapies for patient benefits.