Abstract 1743: Pharmacological sequestration of Skp1 causes degradation of oncogenic E3 ligases and mitotic blockade

Abstract

Abstract Skp1 is an essential adaptor protein of the Skp1-Cul1-F-box protein complex and is able to stabilize the conformation of some ubiquitin E3 ligases. However, the role Skp1 plays during tumorigenesis remains unclear and Skp1-targeting agent is lacking. Here we showed that Skp1 was overexpressed in 33/56 (58.9%) non-small cell lung cancers, and elevated Skp1 was associated with poor prognosis. By structure-based high-throughput virtual screening, we found some Skp1-targeting compounds including 6-O-angeloylplenolin (6-OAP). 6-OAP could bind to Skp1 at sites critical to Skp1-Skp2 interaction, leading to dissociation and proteolysis of oncogenic E3 ligases NIPA, Skp2, and β-TRCP. Consequently, substrates of these E3 ligases Cyclin B1, P27 and E-Cadherin accumulated within the cells and caused prometaphase arrest. 6-OAP exhibited potent anti-lung cancer activity in two murine models and showed low adverse effect. These results indicate that Skp1 is critical to lung cancer pathogenesis, and targeting Skp1 can inactivate crucial oncogenic E3 ligases and exhibits significant therapeutic potentials. Citation Format: Guangbiao Zhou, Yong-Qiang Liu, Jinsong Liu. Pharmacological sequestration of Skp1 causes degradation of oncogenic E3 ligases and mitotic blockade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1743. doi:10.1158/1538-7445.AM2015-1743