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.
Keywords: Cantharidin, antitumor, norcantharidin, PP1, PP2A, structure-activity relationship.
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