Abstract LB-258: Small-molecule inhibitors of de-ubiquitinating enzymes for cervical cancer treatment

Abstract

Abstract Title. Small-Molecule Inhibitors of de-Ubiquitinating Enzymes for Cervical Cancer Treatment Abstract: Human Papillomavirus (HPV) is the primary cause of cervical cancer and responsible for 5% of all cancers worldwide. While HPV vaccines can be an effective preventive measure against cervical cancer, there are currently no virus-specific therapies for it, and the efficacy of standard surgical and chemo/radiotherapies is limited for advanced disease. The E6 oncoprotein of HPV exerts its oncogenic activity by binding to the E3 ubiquitin ligase E6-AP and redirects its activity towards p53 and other tumor suppressor proteins for rapid ubiquitin-mediated proteasomal degradation. Therefore, stabilization of p53 via preventing its ubiquitin-mediated degradation represents a valid therapeutic approach for cervical cancer treatment. De-ubiquitinating enzymes are an attractive novel “druggable” target for cervical cancer as they are responsible for controlling the steady state levels of proteins (i.e. p53 and E6-AP) crucial for maintaining the transformed status of cervical cancer cells, upstream proteasome. Thus, their inhibition is potentially associated with less toxic effects as compared to inhibition of proteasomes. During a structure-based screening of chalcone-based small-molecule inhibitors of ubiquitin-mediated protein degradation we have recently identified a novel class of molecules capable of inhibiting the ubiquitin-mediated protein degradation upstream proteasomes. The lead compound of the series, contains the α-β unsaturated carbonyl system, as the molecular determinant for inhibiting de-ubiquitinating enzyme activities and: i) is capable of inducing acute perturbation of the ubiquitin-mediated protein degradation pathways accompanied by accumulation of poly-ubiquitinated species and reduction of mono-, di-, and tri-ubiquitin species, ii) has no effect on the catalytic activities of purified proteasomes or proteasome in living cells, iii) is capable of induce aggresome formation, iv) is capable of rescuing p53 levels/functions in cervical cancer cells which are accompanied by decrease in the levels of Cyclin D1 and failure for the cells to enter the S-phase of the cell cycle, v) is capable of preventing tumor-colony formation and induces onset of apoptosis via caspase-3 activation in cervical cancer cells without affecting the viability of normal cells. Therefore, we believe in the feasibility of using our lead compound in preclinical model of cervical cancer to test its efficacy as antineoplastic agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-258. doi:10.1158/1538-7445.AM2011-LB-258