NSC 663284

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, arrests cells at both G₁ and G₂/M phases, and prevents the proliferation of several human tumor cell lines.^1,3,4,5

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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. Chem. 44(24), 4042-4049 (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 Ther. 7(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. The Journal of Biological Chemisty 277(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. Ther. 309(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 Res. 27(5A), 3067-3074 (2007).