PPI Modulators of E6 as Potential Targeted Therapeutics for Cervical Cancer: Progress and Challenges in Targeting E6

Abstract

Advanced cervical cancer is primarily managed using cytotoxic therapies, despite evidence of limited efficacy and known toxicity. There is a current lack of alternative therapeutics to treat the disease more effectively. As such, there have been more research endeavors to develop targeted therapies directed at oncogenic host cellular targets over the past 4 decades, but thus far, only marginal gains in survival have been realized. The E6 oncoprotein, a protein of human papillomavirus origin that functionally inactivates various cellular antitumor proteins through protein-protein interactions (PPIs), represents an alternative target and intriguing opportunity to identify novel and potentially effective therapies to treat cervical cancer. Published research has reported a number of peptide and small-molecule modulators targeting the PPIs of E6 in various cell-based models. However, the reported compounds have rarely been well characterized in animal or human subjects. This indicates that while notable progress has been made in targeting E6, more extensive research is needed to accelerate the optimization of leads. In this review, we summarize the current knowledge and understanding of specific E6 PPI inhibition, the progress and challenges being faced, and potential approaches that can be utilized to identify novel and potent PPI inhibitors for cervical cancer treatment.

Keywords: HPV E6; cervical cancer; drug discovery; peptides; protein–protein interactions; small molecules; targeted therapy.

Figure 1

Schematic structure of HPV E6. Two zinc finger domains of E6 are shown, together with regions that are involved in interacting with the cellular substrates indicated above the regions. At the C-terminus is the PDZ-binding motif (PBM) and the associated PDZ proteins that bind to it. (Figure created using Biorender).

Figure 2

Actionable PPIs of E6. Host protein substrates that interact with E6 and the affected downstream effectors and oncogenic signaling are shown. The small-molecule inhibitors that perturb the binding of E6 to these substrates have been identified and are highlighted. The processes that are impacted by these modulators include apoptosis, cell cycle arrest, differentiation, and metastasis. (Figure created using Biorender).