Exploiting protein phosphatase inhibitors based on cantharidin analogues for cancer drug discovery.
Cantharidin (CTD), a natural toxin, can inhibit a variety of tumor cell lines, especially hepatocellular carcinoma cells. It is a strong inhibitor of protein phosphatase type 1 (PP1) and type 2A (PP2A). Because of the cytotoxicity, the clinical application of CDT is limited. Here, we review the structure-activity relationships of CDT analogues, including norcantharidin (NCTD), cantharimides and related derivatives of CTDs, which have more powerful antitumor activity but less cytotoxicity than CDT itself. Important advances in the design of the CTD-based inhibitors achieved recently are outlined here in order to establish principles for synthesis, screening, and the applications of promising anti-cancer drug candidates. In addition, efforts to ameliorate the intrinsic cytotoxicity through the use of drug carriers are also discussed. It is conceivable that rational design of the protein phosphatase inhibitors based on cantharidin analogues can be facilitated by studies of mechanism of the protein-inhibitor interactions and the related structural biology in the future.
Department of Pharmacology, Chemistry and Chemical Engineering Institute, Shaoxing University, Shaoxing, Zhejiang 312000, China. wwdlp@126.com
Liping
L
Deng
Jian
J
Dong
Wei
W
Wang
D002193:Cantharidin / Q000737:chemistry*; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; D002193:Cantharidin