IRC-083864, a novel bis quinone inhibitor of CDC25 phosphatases active against human cancer cells.

CDC25 phosphatases are key actors in cyclin-dependent kinases activation whose role is essential at various stages of the cell cycle. CDC25 expression is upregulated in a number of human cancers. CDC25 phosphatases are therefore thought to represent promising novel targets in cancer therapy.

Pharmacologic inhibition of CDC25 phosphatases impairs interphase microtubule dynamics and mitotic spindle assembly.

The CDC25 cell cycle regulators are promising targets for new pharmacologic approaches in cancer therapy. Inhibitory compounds such as BN82685 have proven to be effective in specifically targeting CDC25 in cultured cells and in inhibiting tumor cell growth. Here, we report that BN82685 impairs microtubule dynamic instability and alters microtubule organization and assembly at the centrosome in interphase cells.

Genotoxic-activated G2-M checkpoint exit is dependent on CDC25B phosphatase expression.

Cell cycle arrest at the G2-M checkpoint is an essential feature of the mechanisms that preserve genomic integrity. CDC25 phosphatases control cell cycle progression by dephosphorylating and activating cyclin-dependent kinase/cyclin complexes. Their activities are, therefore, tightly regulated to modulate cell cycle arrest in response to DNA damage exposure.

Synthesis and biological evaluation of novel heterocyclic quinones as inhibitors of the dual specificity protein phosphatase CDC25C.

A focused set of heterocyclic quinones based on the benzothiazole, benzoxazole, benzimidazole, indazole and isoindole was prepared and screened with respect to the inhibition of the phosphatase activity of CDC25C. Benzoxazole- and benzothiazole-diones were at least 50 times more potent in inhibiting CDC25C than their benzimidazole-indazole- or isoindole-dione counterparts. These in vitro activities were in good correlation with the anti-proliferative effects observed with Mia PaCa-2 and DU-145 human tumor cell cultures.

Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of CDC25 phosphatases.

Cell cycle regulators, such as the CDC25 phosphatases, are potential targets for the development of new anticancer drugs. Here we report the identification and the characterization of BN82685, a quinone-based CDC25 inhibitor that is active in vitro and in vivo. BN82685 inhibits recombinant CDC25A, B, and C phosphatases in vitro.

Synthesis of small molecule CDC25 phosphatases inhibitors.

A targeted library of small molecules has been prepared to optimize the biological activity of BN82002, our initial lead compound, recently described as an original inhibitor of CDC25 phosphatases. Some of these compounds inhibit CDC25 in the micromolar range and therefore reinforce the interest of CDC25 as an anticancer target.

A novel synthetic inhibitor of CDC25 phosphatases: BN82002.

CDC25 dual-specificity phosphatases are essential regulators that dephosphorylate and activate cyclin-dependent kinase/cyclin complexes at key transitions of the cell cycle. CDC25 activity is currently considered to be an interesting target for the development of new antiproliferative agents. Here we report the identification of a new CDC25 inhibitor and the characterization of its effects at the molecular and cellular levels, and in animal models.

A fission yeast strain expressing human CDC25A phosphatase: a tool for selectivity studies of pharmacological inhibitors of CDC25.

Fission yeast is a simple eukaryotic model organism in which many aspects of cell cycle control can be explored. We examined by homologous recombination whether the human CDC25A phosphatase could substitute for the function of the fission yeast Cdc25. We first show: (a).

Inhibitors of the CDC25 phosphatases.

As essential cell cycle regulators, the CDC25 phosphatases are currently considered as potential targets for the development of novel therapeutic approaches. Here, we review the function and regulation of CDC25 phosphatases, their involvement in cancer and Alzheimer's disease, and the properties of several recently identified inhibitors.

Apoptosis and TRAF-1 cleavage in Epstein-Barr virus-positive nasopharyngeal carcinoma cells treated with doxorubicin combined with a farnesyl-transferase inhibitor.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinomas (NPC) are much more sensitive to chemotherapy than other head and neck carcinomas. Spectacular regressions are frequently observed after induction chemotherapy. However, these favorable responses are difficult to predict and often of short duration.