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

Publication ,  Journal Article
Jing, L; Wu, G; Hao, X; Olotu, FA; Kang, D; Chen, CH; Lee, K-H; Soliman, MES; Liu, X; Song, Y; Zhan, P
Published in: Eur J Med Chem
December 1, 2019

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.

Duke Scholars

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

December 1, 2019

Volume

183

Start / End Page

111696

Location

France

Related Subject Headings

  • cdc25 Phosphatases
  • Structure-Activity Relationship
  • Molecular Structure
  • Molecular Dynamics Simulation
  • Medicinal & Biomolecular Chemistry
  • Humans
  • Enzyme Inhibitors
  • Drug Screening Assays, Antitumor
  • Dose-Response Relationship, Drug
  • Combinatorial Chemistry Techniques
 

Citation

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Jing, L., Wu, G., Hao, X., Olotu, F. A., Kang, D., Chen, C. H., … Zhan, P. (2019). Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries. Eur J Med Chem, 183, 111696. https://doi.org/10.1016/j.ejmech.2019.111696
Jing, Lanlan, Gaochan Wu, Xia Hao, Fisayo A. Olotu, Dongwei Kang, Chin Ho Chen, Kuo-Hsiung Lee, et al. “Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries.Eur J Med Chem 183 (December 1, 2019): 111696. https://doi.org/10.1016/j.ejmech.2019.111696.
Jing, Lanlan, et al. “Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries.Eur J Med Chem, vol. 183, Dec. 2019, p. 111696. Pubmed, doi:10.1016/j.ejmech.2019.111696.
Jing L, Wu G, Hao X, Olotu FA, Kang D, Chen CH, Lee K-H, Soliman MES, Liu X, Song Y, Zhan P. Identification of highly potent and selective Cdc25 protein phosphatases inhibitors from miniaturization click-chemistry-based combinatorial libraries. Eur J Med Chem. 2019 Dec 1;183:111696.
Journal cover image

Published In

Eur J Med Chem

DOI

EISSN

1768-3254

Publication Date

December 1, 2019

Volume

183

Start / End Page

111696

Location

France

Related Subject Headings

  • cdc25 Phosphatases
  • Structure-Activity Relationship
  • Molecular Structure
  • Molecular Dynamics Simulation
  • Medicinal & Biomolecular Chemistry
  • Humans
  • Enzyme Inhibitors
  • Drug Screening Assays, Antitumor
  • Dose-Response Relationship, Drug
  • Combinatorial Chemistry Techniques