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

Abstract

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. Here, we report the identification and the characterization of IRC-083864, an original bis-quinone moiety that is a potent and selective inhibitor of CDC25 phosphatases in the low nanomolar range. IRC-083864 inhibits cell proliferation of a number of cell lines, regardless of their resistance to other drugs. It irreversibly inhibits cell proliferation and cell cycle progression and prevents entry into mitosis. In addition, it inhibits the growth of HCT-116 tumor spheroids with induction of p21 and apoptosis. Finally, IRC-083864 reduced tumor growth in mice with established human prostatic and pancreatic tumor xenografts. This study describes a novel compound, which merits further study as a potential anticancer agent. ' 2008 Wiley-Liss, Inc.Key words: CDC25 phosphatase; cell cycle; cancer; pharmacology CDC25 phosphatases dephosphorylate and hence, activate cyclin-dependent kinases (CDKs), thus participating as major actors in the control of cell cycle progression. Their function is also tightly linked to the maintenance of genomic integrity as targets of the checkpoint machinery activated upon DNA injury. 1During the past decade, an increasing body of evidence suggests that CDC25 phosphatases are key players in cell transformation and in cancer progression.2 For instance, when specifically targeted to the mammary gland, overexpression of CDC25B, in association with the carcinogen DMBA (9,10-dimethyl-1,2-benzanthracene), has been shown to induce neoplasia. 3,4 Further, hemizygous disruption of CDC25A inhibits cellular transformation and mammary tumorigenesis in mice, suggesting that a low level of CDC25A protein plays a rate-limiting role in transformation and tumor initiation mediated by oncogene such as H-ras 12 and neu. 5,6 Finally, overexpression of CDC25A and CDC25B proteins has been observed in a wide variety of human tumors (see ref. 2 and 7 for review), and these observations have often been linked to a poor prognosis, suggesting an important role in tumor behavior.A limited number of small molecule inhibitors of the CDC25 phosphatases have been identified (see ref. 1,8 for review), but little is known about either their metabolism or efficacy in xenograft tumor models. These compounds are mainly quinones but also phosphate surrogates or electrophilic entities.9-22 Several mechanisms of action have been proposed for these inhibitors such as oxidization of the catalytic site cysteine, Michael acceptors capable of reacting with the activated thiolate or other electrophilic entities. Initial results support the view that CDC25 is an interesting and important anticancer target, 12,13,23 and considerable effort is currently directed to the identification additional candidate drugs. Here, we describe a novel small molecule...

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“…Many of the most potent CDC25 phosphatase inhibitors reported to date are para-quinonoid-based compounds, such as the vitamin K3 analogues BN82685, NSC 663284, and IRC-083864 12,15,19,21] . The mechanism of the inhibition caused by this kind of inhibitor suggests that these compounds act through the nucleophilic attack of electrophilic entities at a cysteine or at one of the vicinal serines, leading to the covalent modification of the enzyme or the irreversible oxidation of the cysteine present at the active site.…”