Novel therapeutics to treat HPV-associated cancers - human papillomaviruses (HPV) cause very common infections of cutaneous and mucosal epithelia

The National Cancer Institute awarded Kovina Therapeutics Inc. $1,143,891 on August 14, 2026, under the Cancer Treatment Research program (CFDA 93.395) to develop novel therapeutics targeting HPV-16 E6 protein in HPV-associated oropharyngeal, cervical, and anogenital cancers.

Kovina is designing and synthesizing small-molecule compounds that bind to HPV-16 E6 and form covalent bonds with a specific cysteine in the E6 binding pocket for E6AP, blocking the E6–E6AP interaction that normally leads to proteasome-mediated destruction of the tumor suppressor protein P53. The compounds restore wild-type P53 levels and function selectively in HPV-positive cells and induce death of HPV-16-expressing cells. The research employs iterative optimization guided by co-crystallization and in silico docking to design chemotypes that block E6 interaction with E6AP and restore P53 function.

Performance runs through July 31, 2028, at Kovina's Indianapolis, Indiana location. The award funds research in discovery and development of molecularly targeted therapies for cancer treatment, consistent with the Cancer Treatment Research program's mandate to develop improved methods of cancer treatment through fundamental and applied laboratory research.

Infection with specific "high risk" HPV types can progress to premalignant lesions called dysplasias, which over a period of years, can eventuate in invasive and metastatic oropharyngeal, cervical and anogenital malignancies that are challenging to effectively treat and have a poor 5-year survival. The current standard of care for HPV induced cancers is a combination of surgery, radiation and chemotherapy. Immunotherapy is also used on a limited basis with slight improvement in outcomes. Existing treatment options can lead to debilitating side effects. Kovina therapeutics' goal is to bring to market the first medication that specifically targets HPV driven cancers of the oropharynx, cervix, and anus. Our strategy is to selectively inactivate the HPV-16 E6 protein. 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 cellular ubiquitin ligase E6AP. In a trimolecular complex with HPV E6, E6AP 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; 2) are armed with a 'warhead' to make a covalent bond with a specific cysteine in the HPV-16 E6 binding pocket for E6AP; and 3) restore levels of wild-type activated P53 only in HPV+ cells. Iterative optimization guided by CO- crystallization and in silico docking strategies enabled design and synthesis of chemotypes HAT block E6 interaction with E6AP, restore P53 levels and function, and induce death of HPV-16 expressing cells. Proof-of-concept experiments in immunodeficient mice demonstrate successful inhibition of tumor growth with several HPV-16 expressing human cancer derived cell lines. Early adme and pharmacologic testing was used to screen these candidates. This two-year direct phase II sbir proposal seeks to establish the optimal formulation for systemic delivery of the drug. Process optimization, CMC, adme, and toxicology will direct our 'go/no go' selection of a lead clinical candidate. These plans are designed to fulfill FDA guidelines for a systemic agent. Successful completion of these IND-enabling phase II sbir studies advance kovina's efforts to eventually submit an IND application to the FDA and prepare for a first-in-human clinical trial to treat HPV induced cancers.