ABSTRACT “High-risk” human papillomavirus (HPV) types such as 16 (HPV-16) are identified in the majority of HPV-associated pre-malignant and malignant pathologies of cervical, anogenital, and oropharyngeal epithelia. The E6 protein is essential for viral replication. Structure-based computational screening followed by design and synthesis of derivatives led to the identification of a series of small molecules that bind to the HPV-16 E6 protein and inhibits its association with the E6AP ubiquitin ligase in vitro as well as E6-mediated p53 degradation in cells. Using iterative cycles of structure based drug design and rigorous biochemical assays, Kovina Therapeutics’ academic collaborators have identified more potent E6 inhibitory compounds. Kovina has an exclusive worldwide license to these discoveries. The objective of this STTR application is to characterize the pharmacokinetic properties of these unique E6 inhibitors and identify the best candidates for advancement as therapeutics. Specific inhibition of growth of HPV-16 xenograft tumors will serve as proof of concept validation for our lead candidates. We are ideally positioned to perform and complete requisite pharmacokinetic, pharmacologic and toxicologic studies in the SBIR phase, leading to IND-enabling selection of a clinical lead. Having developed and executed the experiments described in this project, the PI, Dr. Anne Rietz, is superbly suited to continue these investigations. She will be mentored by senior leaders from academia and the drug industry. Kovina’s CEO and Board Chair, who have successfully grown and managed two biotech companies that were acquired, will also mentor Dr. Rietz. Along with other mentoring venues and business school courses, Dr. Rietz will transition to a career in corporate drug development.