SMALL MOLECULES TARGETING HPV E6 AND E7 ONCOPROTEINS EXPRESSION

Infection with high-risk human papillomavirus (HPV) is responsible for the induction of cervical cancer (CC), one of the most common malignancies for incidence and mortality in female population worldwide.(1) The HPV E6 and E7 proteins play a key role in the transformation of primary human keratinocytes into malignant cells by abrogating the function of tumor suppressor proteins p53 and pRb. The continuous expression of these oncoproteins proved to be necessary for the maintenance of the transformed phenotype, representing an ideal molecular target for the development of innovative anti-CC therapies.(2) While macromolecule-based approaches have proved to be effective in silencing this expression,(3,4) the development of small molecules remains highly desirable. The availability of a large series of quinolone-based compounds endowed with antiviral activity due to the inhibition of viral transactivation, prompted us to test their ability to reduce the E6 and E7 transcription using a cell based high-throughput assay previously developed by us.(5) Some of the tested compounds were active in inhibiting HPV-16 long control region activity with IC50 values in the low micromolar range at no toxic concentrations. The ability to downregulate E6 and E7 mRNA transcripts was confirmed in a RT-PCR assay using CaSki cells, that are HPV-16 positive cervical carcinoma-derived cells. Starting from the most promising derivative, an enlarged series of analogues were designed, synthesized and biologically tested leading to identify more potent compounds and delineate a preliminary structure-activity relationship.