From Academia to Business: Development of Novel Therapeutics Against HPV-Associated Cancer

摘要 在宫颈、肛门生殖器和口咽上皮的大多数HPV相关的癌前病变和恶性病变中鉴定出“高危”人乳头瘤病毒（HPV）类型，例如16（HPV-16）。的 E6蛋白是病毒复制所必需的。基于结构的计算筛选，然后进行设计， 衍生物的合成导致了一系列与HPV-16 E6结合的小分子的鉴定 在体外抑制其与E6 AP泛素连接酶的结合以及E6介导的p53 细胞内降解。使用基于结构的药物设计和严格的生化分析的迭代循环， Kopped Therapeutics的学术合作者已经确定了更有效的E6抑制化合物。科什 拥有这些发现的全球独家许可。此STTR应用程序的目的是 表征这些独特的E6抑制剂的药代动力学特性，并确定最佳候选人， 作为治疗方法的进步。HPV-16异种移植肿瘤生长的特异性抑制将作为HPV-16异种移植肿瘤生长的证据。 为我们的主要候选人进行概念验证。我们是执行和完成必要的 SBIR阶段的药代动力学、药理学和毒理学研究，导致IND选择 一个临床领先者。在开发和执行了本项目中描述的实验后，PI Anne博士 里茨，是非常适合继续这些调查。她将接受来自以下国家的高级领导人的指导 学术界和制药业。Koombo的首席执行官和董事会主席，他们成功地成长和管理 两家被收购的生物技术公司也将指导里茨博士。沿着其他辅导场所， 商学院的课程，博士Rietz将过渡到企业药物开发的职业生涯。

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.