Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries.

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.
PMID: 31541869 [PubMed - as supplied by publisher]

Source: European Journal of Medicinal Chemistry - September 13, 2019 Category: Chemistry Authors: Jing L, Wu G, Hao X, Olotu FA, Kang D, Chen CH, Lee KH, Soliman MES, Liu X, Song Y, Zhan P Tags: Eur J Med Chem Source Type: research