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Dual G1 and G2/M phase inhibition by SC-ααδ9, a combinatorially derived Cdc25 phosphatase inhibitor

Oncogene volume 18, pages 6989–6996 (1999)Cite this article

Abstract

The Cdc25 dual specificity phosphatase family has a central role in controlling cell cycle progression and has been implicated in the etiology of cancer. One compound, 4-(benzyl-(2-[(2, 5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylamino butyric acid (SC-ααδ9), was previously identified as the most potent reported synthetic inhibitor of Cdc25 phosphatases in vitro. In the present study, we demonstrate that SC-ααδ9 inhibited Cdc25-dependent cell cycle progression at both G1 and G2/M phase using tsFT210 cells, which express a temperature-sensitive Cdc2 mutant. SC-ααδ9 blocked both G2/M transition and dephosphorylation of Cdc2 in a concentration-dependent manner. SC-ααδ9 also enhanced tyrosine phosphorylation of both Cdk2 and Cdk4, and decreased Cdk4 kinase activity. Both of the kinases are potent regulators of G1 transition. Furthermore, closely related chemical analogs that lacked Cdc25 inhibitory activity failed to block cell cycle progression at both G1 and G2/M, and did not affect Cdc2 phosphorylation or Cdk4 kinase activity. SC-ααδ9 did not alter p53, p21 or p16 levels. Our results support the hypothesis that the disruption in cell cycle transition caused by SC-ααδ9 was due to intracellular Cdc25 inhibition. We propose that the SC-αad9 pharmacophore could be useful in further clarifying the role of Cdc25 phosphatase-dependent pathways in checkpoint control, oncogenesis, and apoptosis.

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Acknowledgements

We thank Andreas Vogt, Iliya M Lefterov, Radosveda P Koldamova, Susana E Montoya, Eileen Southwick, Angela Wang and the other members of Lazo Laboratory for their comments and scientific support. We also thank Professor Michio Yamakido at Hiroshima University for his assistance. This work is dedicated to the memory of Emily E Dorrance. May we all fight cancer with her spirit.

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Authors and Affiliations

  1. Department of Pharmacology, University of Pittsburgh, Pittsburgh, 15261, Pennsylvania, PA, USA

    Kenji Tamura, Robert L Rice & John S Lazo

  2. Department of Chemistry, University of Pittsburgh, Pittsburgh, 15261, Pennsylvania, PA, USA

    Peter Wipf

  3. Second Department of Internal Medicine, Hiroshima University School of Medicine, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734, Japan

    Kenji Tamura

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  1. Kenji Tamura
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Tamura, K., Rice, R., Wipf, P. et al. Dual G1 and G2/M phase inhibition by SC-ααδ9, a combinatorially derived Cdc25 phosphatase inhibitor. Oncogene 18, 6989–6996 (1999). https://doi.org/10.1038/sj.onc.1203179

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