Abstract
Inhibition of Cdc25 phosphatases is a strategy for the discovery and development of novel anticancer agents targeting the cell cycle. A number of potent small molecule Cdc25 inhibitors have been identified. They are derived from different chemical classes; the most potent and selective derivatives are quinones. The electrophilic properties of quinones suggest the possibility of inducing a sulphydryl arylation of a cysteine in the enzyme active site. It is also possible that inhibition is due to redox cycling activity and production of ROS. Thus, oxidation of the thiolate form of cysteine occurs, leading to inactivation of enzymatic activity. Many of these inhibitors are active on all three Cdc25 phosphatases, cause cell cycle arrest and inhibit the growth of several human tumor cell lines. The possibility of toxicities induced by ROS, prompted the search for non-quinoid antagonists. It is not yet clear how these compounds bind within the enzymes active site. Generally, electrophilic moieties able to trap the catalytic cysteine play an important role. Another strategy for identifying Cdc25 inhibitors is the development of compounds able to interact with the conserved loop region instead of phosphate. In this review a summary of the most interesting Cdc25 inhibitors is given together with their biological activity. SAR studies concerning the importance of some structural features will be described.
Keywords: antiproliferative activity, SAR, cell cycle, quinones, Cdc25 phosphatase
Current Medicinal Chemistry
Title: Synthetic Small Molecule Cdc25 Phosphatases Inhibitors
Volume: 15 Issue: 6
Author(s): Daniela Pizzirani, Laura Garuti and Marinella Roberti
Affiliation:
Keywords: antiproliferative activity, SAR, cell cycle, quinones, Cdc25 phosphatase
Abstract: Inhibition of Cdc25 phosphatases is a strategy for the discovery and development of novel anticancer agents targeting the cell cycle. A number of potent small molecule Cdc25 inhibitors have been identified. They are derived from different chemical classes; the most potent and selective derivatives are quinones. The electrophilic properties of quinones suggest the possibility of inducing a sulphydryl arylation of a cysteine in the enzyme active site. It is also possible that inhibition is due to redox cycling activity and production of ROS. Thus, oxidation of the thiolate form of cysteine occurs, leading to inactivation of enzymatic activity. Many of these inhibitors are active on all three Cdc25 phosphatases, cause cell cycle arrest and inhibit the growth of several human tumor cell lines. The possibility of toxicities induced by ROS, prompted the search for non-quinoid antagonists. It is not yet clear how these compounds bind within the enzymes active site. Generally, electrophilic moieties able to trap the catalytic cysteine play an important role. Another strategy for identifying Cdc25 inhibitors is the development of compounds able to interact with the conserved loop region instead of phosphate. In this review a summary of the most interesting Cdc25 inhibitors is given together with their biological activity. SAR studies concerning the importance of some structural features will be described.
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Cite this article as:
Pizzirani Daniela, Garuti Laura and Roberti Marinella, Synthetic Small Molecule Cdc25 Phosphatases Inhibitors, Current Medicinal Chemistry 2008; 15 (6) . https://dx.doi.org/10.2174/092986708783769722
DOI https://dx.doi.org/10.2174/092986708783769722 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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