Skp1 in lung cancer: clinical significance and therapeutic efficacy of its small molecule inhibitors.

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 36/64 (56.3%) of 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 molecules including a natural compound 6-O-angeloylplenolin (6-OAP). 6-OAP bound Skp1 at sites critical to Skp1-Skp2 interaction, leading to dissociation and proteolysis of oncogenic E3 ligases NIPA, Skp2, and ß-TRCP, and accumulation of their substrates Cyclin B1, P27 and E-Cadherin. 6-OAP induced prometaphase arrest and exerted 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 Skp1 inhibitor inactivates crucial oncogenic E3 ligases and exhibits significant therapeutic potentials.

Petchienes A-E, Meroterpenoids from Ganoderma petchii.

Petchienes A-E (1-5), five new meroterpenoids, were isolated from the fruiting bodies of Ganoderma petchii. Their structures, including absolute configurations, were elucidated by means of spectroscopic and computational methods. Compound 4 was isolated as a racemic mixture, which was finally purified by chiral HPLC to yield individual (-) and (+)-antipodes. Biological evaluation showed that compounds 2 and (-)-4 could increase intracellular free calcium concentration at 10 µM in HEK-293 cells.