Modeling of cantharidin and fostriecin towards the development of anti-tumor drugs

Cantharidin, a natural product produced by blister beetles, has been used for over 2000 years as a traditional medicine in China. Fostriecin is a natural antibiotic produced by Streptomyces pulveraceus, showing anti-tumor properties. The biological activity of both compounds resides in their ability to function as inhibitors of human serine/threonine protein phosphatase types 1, 2A, 2B, 4, 5, 6 (PPases), however, with toxic-side effects. To decrease toxicity, the development of more selective inhibitors is desired. In this study, a computer-model was employed to predict the binding of cantharidin, 84 analogues of cantharidin, and fostriecin to PP1, PP5 and PP2A. The predictions of cantharidin/PPase and fostriecin/PPase binding were validated by inhibition studies and site-directed mutagenesis approach, respectively. Together, these studies suggest that the synthesis of novel-derivatives of cantharidin and fostriecin with greater potency, stability and selectivity can be developed and the development process may benefit from such computer based models.