NSC-663284

Description: NSC-663284 (also known as SPS-8I1; DA3003-1) is a novel and potent inhibitor of the Cdc25 dual specificity phosphatases with an IC50 of 0.21 uM. NSC 663284 blocked cellular Erk dephosphorylation caused by ectopic Cdc25A expression. The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signaling processes and cell proliferation, but potent and selective inhibitors are lacking. DA3003-1 inhibited the growth of subcutaneous human colon HT29 xenografts in SCID mice. After a single i.v. dose of 5 mg/kg, DA3003-1 was not detectable in plasma or tissues beyond 5 min. In vitro studies showed that DA3003-1 was rapidly dechlorinated and conjugated to glutathione. Following DA3003-1 treatment of tumor-bearing SCID mice, reduced glutathione concentrations in HT29 tumor were decreased to a greater extent and remained decreased for longer than the reduced glutathione concentrations in liver and kidneys. These studies suggest that the minimal antitumor activity of DA3003-1 in mice may be due to its rapid metabolism.

References: J Med Chem. 2001 Nov 22; 44(24):4042-9.; Anticancer Res. 2007 Sep-Oct; 27(5A):3067-73.