Characterization of small-molecule inhibitors targeting E7 oncoprotein of human papillomavirus

Human papillomaviruses (HPVs) are small double-stranded DNA viruses with an epithelial tropism. The high-risk HPV genotypes (HR-HPVs) are responsible for almost all cervical carcinomas worldwide. Although an extensive vaccination campaign has been started, specific treatments for already infected patients are needed since no specific anti-HPV drugs exist yet. The oncogenic properties of HR-HPVs are mainly related to E6 and E7 oncoproteins. E7 interacts with pRb, an oncosuppressor that controls cell cycle progression, and induces its proteasomal degradation. Another target of degradation by E7 is PTPN14, an inhibitor of YAP. Previously, our group discovered the small molecule Cpd20 as an inhibitor of the E7-PTPN14 interaction. Additionally, two other compounds, Cpd23 and Cpd28, could inhibit E7-PTPN14 interaction although they did not rescue PTPN14 levels. In this work, to find compounds with better activity, analogs of Cpd20, Cpd23, and Cpd28 were tested to assess their cytotoxic activity against HPV-positive cells, and their ability to inhibit E7-PTPN14 interaction and rescue PTPN14 levels. In addition, our group discovered that Cpd28 can rescue pRb levels. In this work, analogs of Cpd28 were tested for their ability to rescue pRb levels in HPV-positive cells by Western blot experiments. Furthermore, some antitumoral properties of Cpd28 were characterized.