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

从学术界到商界：针对 HPV 相关癌症的新型疗法的开发

• 批准号: 10813323
• 负责人: Anne Rietz
• 金额: $ 90.97万
• 依托单位: KOVINA THERAPEUTICS INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10813323
• 关键词: Academia; Affinity; Algorithms; Antiviral Agents; Binding; Biochemical; Biological Assay; Biotechnology; Businesses; Cancer cell line; Canis familiaris; Cell Culture Techniques; Cell Proliferation; Cell Survival; Cells; Cervical; Chemistry; Clinical; Clinical Trials; Complex; Coupled; Cysteine; Cytochrome P450; Data; Development; Dose; Drug Design; Drug Industry; Drug Kinetics; Epithelium; Evaluation; Exhibits; Fluorescence Polarization; Funding; Good Manufacturing Process; Growth; HPV-High Risk; Human; Human Papilloma Virus Vaccine; Human Papilloma Virus-Related Malignant Neoplasm; Human Papillomavirus; Human papilloma virus infection; Immunocompromised Host; Immunodeficient Mouse; In Vitro; Infection; Interferometry; Investigation; Lead; Licensing; Liver Microsomes; Malignant - descriptor; Malignant Neoplasms; Malignant Vaginal Neoplasm; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Malignant neoplasm of penis; Malignant neoplasm of vulva; Mass Spectrum Analysis; Maximum Tolerated Dose; Mediating; Medical; Mentors; Metabolism; Microsomes; Molecular; Mus; Neoplastic Cell Transformation; Oral; Oropharyngeal; Outcome; Pathology; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacotherapy; Phase; Plasma; Positioning Attribute; Prevention; Property; Proteins; Rattus; Roentgen Rays; Route; Safety; Schools; Series; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Structure; Surface; TP53 gene; Testing; Therapeutic; Toxic effect; Toxicology; Tumor Cell Line; Tumor Suppressor Proteins; UBE3A gene; Ubiquitination; Validation; Viral Genome; Viral Proteins; Virus Diseases; Virus Replication; Woman; Xenograft Model; adduct; cancer cell; career; cell growth; cellular targeting; chronic infection; covalent bond; design; dosage; drug candidate; drug development; drug-like compound; experience; experimental study; high risk; in silico; in vitro activity; in vivo; inhibitor; interdisciplinary approach; intravenous administration; iterative design; lead candidate; lead optimization; malignant oropharynx neoplasm; manufacture; meter; multicatalytic endopeptidase complex; novel therapeutics; pharmacokinetic model; pharmacologic; phase 1 study; premalignant; prevent; scaffold; screening; small molecule; small molecule libraries; subcutaneous; time use; tumor; tumor growth; tumor xenograft; ubiquitin ligase

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.

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 蛋白质并抑制其与体外E6 AP遍在蛋白连接酶以及E6介导的p53的结合 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。