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Small Molecule E6 Inhibitors to Treat Dysplasia Caused by HPV Infections

小分子 E6 抑制剂治疗 HPV 感染引起的发育异常

基本信息

批准号：
10390563
负责人：
ELLIOT J. ANDROPHY
金额：
$ 29.85万
依托单位：
KOVINA THERAPEUTICS INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10390563
关键词：
Animal Model Antiviral Agents Anus Apoptosis Applications Grants Attention Binding Biochemical Biological Biological Assay Cells Cervical Cervix Uteri Cessation of life Clinical Collection Complex Coupled Cream Crystallization Cysteine Data Drug Kinetics Drug Targeting Dysplasia Epithelial Evaluation Formulation Gel Genital Genitalia Genotype Goals Guidelines HIV Human Human Papilloma Virus Vaccine Human Papillomavirus Human papilloma virus infection Human papillomavirus 16 In Vitro Infection Infectious Skin Diseases Inflammatory Response Investigation Lead Lesion Liver Microsomes Lotion Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of cervix uteri Measures Mediating Medical Molecular Weight Morbidity - disease rate Mucous Membrane Mus Neoplastic Cell Transformation Ointments Operative Surgical Procedures Pain Pharmaceutical Preparations Pharmacotherapy Phase Population Positioning Attribute Procedures Process Property Proteins Safety Series Skin Small Business Innovation Research Grant Small Molecule Chemical Library Solubility Specific qualifier value TP53 gene Testing Therapeutic Topical agent Topical application Toxic effect Toxicology Tumor Suppressor Proteins UBE3A gene Ubiquitination Vagina Viral Genome Virus Virus Diseases Vulva Wait Time Woman Work X-Ray Crystallography adduct base cancer invasiveness cellular targeting covalent bond design drug development experimental study high risk in silico in vivo inhibitor intraepithelial men metabolic abnormality assessment model design model development multicatalytic endopeptidase complex novel pharmacokinetic model phase 1 study premalignant prevent prophylactic protein protein interaction prototype screening small molecule small molecule libraries standard of care success systemic toxicity ubiquitin ligase

项目摘要

Human papillomaviruses (HPV) cause exceedingly common infections of cutaneous and mucosal epithelia. Infection with specific “high risk” HPV genotypes can progress to pre- malignant lesions called dysplasias, which over a period of years, can eventuate in invasive and metastatic epithelial malignancies. Our therapeutic goal is to treat early stage infections of the cervix, genitalia, and anus that afflict millions of women and men before these progress to invasive cancers. Kovina Therapeutics strategy is to eliminate HPV infection by selectively targeting the E6 protein and preventing interactions with its cellular binding partners. E6 is necessary for viral genome replication and maintenance and is always expressed in HPV-associated dysplasia and malignancies. We performed in silico screening of chemical libraries for small molecules that would resemble the interface of E6 with several of its cellular partners. Our assays focused on the protein-protein interaction of E6 with the ubiquitin ligase E6AP, which mediates ubiquitination and proteasome mediated destruction of the tumor suppressor protein p53. Using this model, we designed and synthesized compounds that 1) bind to HPV-16 E6 and 2) are armed with a ‘warhead’ to make a covalent bond with a specific cysteine in HPV-16 E6 binding pocket for E6AP. The approach to identify molecules equipped with reactive warheads that mediate covalent and irreversible binding to cysteine is exemplified in several new clinically available drugs that target proteins previously considered undruggable. We discovered several compounds covalently bound to E6 via this cysteine residue, block E6 interaction with E6AP, restore P53 function, and induce death of HPV-16 expressing cells. Multiple biochemical analyses including X-ray crystallography prove these inhibitors occupy the targeted E6 pocket and form a single adduct with this cysteine. Iterative optimization guided by the co-crystal data enabled design and synthesis of >80 novel compounds and has resulted chemotypes with increased activity. This one-year Phase I SBIR proposal plans to screen our existing E6 inhibitor collection to determine their biological activities in cell-based assays and pharmacokinetic properties that would meet FDA guidelines for a topical agent. We will initiate drug development studies including formulation for topical application and early stage pharmacokinetic and toxicology characterization. The success of Phase I study will validate this antiviral strategy and position us to proceed to apply for a Phase II SBIR to perform IND-enabling studies.

人乳头瘤病毒（HPV）引起极为常见的皮肤和皮肤感染