A novel small-molecule inhibitor of the human papillomavirus E6-p53 interaction that reactivates p53 function and blocks cancer cells growth

GORACCI, LAURA; SPYRAKIS, FRANCESCA; TRAVÉ, GILLES; PALÙ, GIORGIO; MESSA, LORENZO; BERTAGNIN, CHIARA; COUSIDO-SIAH, ALEXANDRA; CRUCIANI, GABRIELE; CELEGATO, MARTA; MERCORELLI, BEATRICE; SUAREZ, IRINA; BANKS, LAWRENCE; LOREGIAN, ARIANNA

CANCER LETTERS

ELSEVIER IRELAND LTD

Año: 2020 vol. 470 p. 115 - 125

0304-3835

Despite prophylactic vaccination campaigns, human papillomavirus (HPV)-induced cancers still represent amajor medical issue for global population, thus specific anti-HPV drugs are needed. Since the ability of HPV E6oncoprotein to promote p53 degradation is linked to tumor progression, E6 has been proposed as an ideal targetfor cancer treatment. Using the crystal structure of the E6/E6AP/p53 complex, we performed an in silicoscreening of small-molecule libraries against a highly conserved alpha-helix in the N-terminal domain of E6involved in the E6-p53 interaction. We discovered a compound able to inhibit the E6-mediated degradation ofp53 through disruption of E6-p53 binding both in vitro and in cells. This compound could restore p53 intracellularlevels and transcriptional activity, reduce the viability and proliferation of HPV-positive cancer cells,and block 3D cervospheres formation. Mechanistic studies revealed that the compound anti-tumor activitymainly relies on induction of cell cycle arrest and senescence. Our data demonstrate that the disruption of thedirect E6-p53 interaction can be obtained with a small-molecule compound leading to specific antitumoralactivity in HPV-positive cancer cells and thus represents a new approach for anti-HPV drug development.