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Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization
Lanlan Jing1, Gaochan Wu1, Xia Hao1
1Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Ji'nan, Shandong, PR China.
Abstract:
Cell division cycle 25 (Cdc25) protein phosphatases play key roles in the transition between the cell cycle phases and their association with various cancers has been widely proven, which makes them ideal targets for anti-cancer treatment. Though several Cdc25 inhibitors have been developed, most of them displayed low activity and poor subtype selectivity. Therefore, it is extremely important to discover novel small molecule inhibitors with potent activities and significant selectivity for Cdc25 subtypes, not only served as drugs to treat cancer but also to probe its mechanism in transitions. In this study, miniaturized parallel click chemistry synthesis via CuAAC reaction followed by in situ biological screening were used to discover selective Cdc25 inhibitors. The bioassay results showed that compound M2N12 proved to be the most potent Cdc25 inhibitor, which also act as a highly selective Cdc25C inhibitor and was about 9-fold potent than that of NSC 663284. Moreover, M2N12 showed remarkable anti-growth activity against the KB-VIN cell line, equivalent to that of PXL and NSC 663284. An all-atom molecular dynamics (MD) simulation approach was further employed to probe the significant selectivity of M2N12 for Cdc25C relative to its structural homologs Cdc25A and Cdc25B. Overall, above results make M2N12 a promising lead compound for further investigation and structural modification.
Insights
Researchers discovered a potent and selective Cdc25C inhibitor, M2N12, using click chemistry. This novel compound shows significant anti-cancer activity and offers a promising lead for developing new cancer therapies targeting cell division.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Molecular Biology
Background:
- Cell division cycle 25 (Cdc25) phosphatases are crucial regulators of cell cycle progression.
- Dysregulation of Cdc25 is implicated in various cancers, making them attractive therapeutic targets.
- Existing Cdc25 inhibitors often lack sufficient potency and subtype selectivity.
Purpose of the Study:
- To discover novel small molecule inhibitors targeting Cdc25 protein phosphatases.
- To identify inhibitors with potent activity and high selectivity for Cdc25 subtypes.
- To explore the potential of these inhibitors as anti-cancer agents.
Main Methods:
- Miniaturized parallel click chemistry synthesis utilizing the CuAAC reaction.
- In situ biological screening of synthesized compounds.
- Molecular dynamics (MD) simulations to investigate binding selectivity.
Main Results:
- Compound M2N12 emerged as the most potent inhibitor of Cdc25.
- M2N12 demonstrated high selectivity for Cdc25C, outperforming existing compounds.
- M2N12 exhibited significant anti-growth activity against the KB-VIN cell line.
- MD simulations elucidated the molecular basis for M2N12's selective binding to Cdc25C.
Conclusions:
- M2N12 is a highly potent and selective Cdc25C inhibitor.
- M2N12 represents a promising lead compound for developing novel anti-cancer therapeutics.
- Further structural modification and investigation of M2N12 are warranted.
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