Three genes encode dual specificity phosphatases that are Cdc25 homologs. The phosphatases, Cdc25A through C, are proto-oncogenes and are often over-expressed in cancers. NSC 663284 is a potent, cell-permeable, and irreversible inhibitor of all Cdc25 isoforms, with preference for Cdc25A (IC50 = 29, 95, and 89 nM for Cdc25A, Cdc25B2, and Cdc25C, respectively).1 NSC 663284 poorly inhibits other phosphatases, including Vaccinia virus VH1-related (IC50 = 4.0 μM), PTP1B (no inhibition), and the mitogen-activated protein kinase phosphatases (MKP) MKP-1 or -3 (no inhibition).1,2 By inhibiting Cdc25 isoforms, NSC 663284 prevents the dephosphorylation and activation of Cdk1 and Cdk2,3,4 arrests cells at both G1 and G2/M phases,3 and prevents the proliferation of several human tumor cell lines.1,3,5
1
Lazo, J.S., Aslan, D.C., Southwick, E.C., et al. Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25. J Med Chem444042-4049(2001).
2
Vogt, A., McDonald, P.R., Tamewitz, A., et al. A cell-active inhibitor of mitogen-activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells. Mol Cancer Ther7(2)330-340(2008).
3
Pu, L., Amoscato, A.A., Bier, M.E., et al. Dual G1 and G2 phase inhibition by a novel, selective Cdc25 inhibitor 7-chloro-6-(2-morpholin-4-ylethylamino)-quinoline-5,8-dione. J Biol Chem277(49)46877-46885(2002).
4
Han, Y., Shen, H., Carr, B.I., et al. NAD(P)H:quinone oxidoreductase-1-dependent and -independent cytotoxicity of potent quinone Cdc25 phosphatase inhibitors. J Pharmacol Exp Ther309(1)64-70(2004).
5
Guo, J., Parise, R.A., Joseph, E., et al. Pharmacology and antitumor activity of a quinolinedione Cdc25 phosphatase inhibitor DA3003-1 (NSC 663284). Anticancer Res273067-3074(2007).
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ClC1=C(NCCN2CCOCC2)C(=O)c2ncccc2C1=O
Background Reading
Vogt, A., McDonald, P.R., Tamewitz, A., et al. A cell-active inhibitor of mitogen-activated protein kinase phosphatases restores paclitaxel-induced apoptosis in dexamethasone-protected cancer cells. Mol Cancer Ther7(2)330-340(2008).
Han, Y., Shen, H., Carr, B.I., et al. NAD(P)H:quinone oxidoreductase-1-dependent and -independent cytotoxicity of potent quinone Cdc25 phosphatase inhibitors. J Pharmacol Exp Ther309(1)64-70(2004).
Pu, L., Amoscato, A.A., Bier, M.E., et al. Dual G1 and G2 phase inhibition by a novel, selective Cdc25 inhibitor 7-chloro-6-(2-morpholin-4-ylethylamino)-quinoline-5,8-dione. J Biol Chem277(49)46877-46885(2002).
Guo, J., Parise, R.A., Joseph, E., et al. Pharmacology and antitumor activity of a quinolinedione Cdc25 phosphatase inhibitor DA3003-1 (NSC 663284). Anticancer Res273067-3074(2007).
Lazo, J.S., Aslan, D.C., Southwick, E.C., et al. Discovery and biological evaluation of a new family of potent inhibitors of the dual specificity protein phosphatase Cdc25. J Med Chem444042-4049(2001).