Abstract
Aim:
Cell division cycle 25 (CDC25) phosphatases have recently been considered as potential targets for the development of new cancer therapeutic agents. We aimed to discover novel CDC25B inhibitors in the present study.
Methods:
A molecular level high-throughput screening (HTS) assay was set up to screen a set of 48000 pure compounds.
Results:
HTS, whose average Z′ factor is 0.55, was finished and LGH00045, a mixed-type CDC25B inhibitor with a novel structure and relative selectivity for protein tyrosine phosphatases, was identified. Furthermore, LGH00045 impaired the proliferation of tumor cells and increased cyclin-dependent kinase 1 inhibitory tyrosine phosphorylation. In synchronized HeLa cells, LGH00045 delayed cell cycle progression at the G2–M transition.
Conclusion:
LGH00045, a novel CDC25B inhibitor identified through HTS, showed good inhibition on the proliferation of tumor cells and affected the cell cycle progression, which makes it a good hit for further structure modification.
Similar content being viewed by others
Article PDF
References
Cao S, Foster C, Brisson M, Lazo JS, Kingston DG . Halenaquinone and xestoquinone derivatives, inhibitors of CDC25B phosphatase from a Xestospongia sp. Bioorg Med Chem 2005; 13: 999–1003.
Mailand N, Falck J, Lukas C, Syljuåsen RG, Welcker M, Lukas J . Rapid destruction of human CDC25A in response to DNA damage. Science 2000; 288: 1425–9.
Nilsson I, Hoffmann I . Cell cycle regulation by the CDC25 phosphatase family. Prog Cell Cycle Res 2000; 4: 107–14.
Turowski P, Franckhauser C, Morris MC, Vaglio P, Fernandez A, Lamb NJ . Functional CDC25C dual-specificity phosphatase is required for S-phase entry in human cells. Mol Biol Cell 2003; 14: 2984–98.
Lyon MA, Ducret AP, Wipf P, Lazo JS . Dual-specificity phosphatases as targets for antineoplastic agents. Nat Rev Drug Discov 2002; 1: 961–76.
Cangi MG, Cukor B, Soung P, Signoretti S, Moreira G Jr, Ranashinge M, et al. Role of the CDC25A phosphatase in human breast cancer. J Clin Invest 2000; 106: 753–61.
Broggini M, Buraggi G, Brenna A, Riva L, Codegoni AM, Torri V, et al. Cell cycle-related phosphatases CDC25A and B expression correlates with survival in ovarian cancer patients. Anticancer Res 2000; 20: 4835–40.
Ngan ES, Hashimoto Y, Ma ZQ, Tsai MJ, Tsai SY . Overexpression of CDC25B, an androgen receptor coactivator, in prostate cancer. On-cogene 2003; 22: 734–9.
Sasaki H, Yukiue H, Kobayashi Y, Tanahashi M, Moriyama S, Na-kashima Y, et al. Expression of the CDC25B gene as a prognosis marker in non-small cell lung cancer. Cancer Lett 2001; 173: 187–92.
Talvinen K, Tuikkala J, Grönroos J, Huhtinen H, Kronqvist P, Aittokallio T, et al. Biochemical and clinical approaches in evaluating the prognosis of colon cancer. Anticancer Res 2006; 26: 4745–51.
Sato Y, Sasaki H, Kondo S, Fukai I, Kiriyama M, Yamakawa Y, et al. Expression of the CDC25B mRNA correlated with that of N-myc in neuroblastoma. Jpn J Clin Oncol 2001; 31: 428–31.
Galaktionov K, Lee AK, Eckstein J, Draetta G, Meckler J, Loda M, et al. CDC25 phosphatases as potential human oncogenes. Science 1995; 269: 1575–7.
Ma ZQ, Chua SS, DeMayo FJ, Tsai SY . Induction of mammary gland hyperplasia in transgenic mice over-expressing human CDC25B. Oncogene 1999; 18: 4564–76.
Yao Y, Slosberg ED, Wang L, Hibshoosh H, Zhang YJ, Xing WQ, et al. Increased susceptibility to carcinogeninduced mammary tumors in MMTV- CDC25B transgenic mice. Oncogene 1999; 18: 5159–66.
Millar JB, Blevitt J, Gerace L, Sadhu K, Featherstone C, Russell P . p55CDC25 is a nuclear phosphoprotein required for the initiation of mitosis in human cells. Proc Natl Acad Sci USA 1991; 88: 10 500–4.
Lammer C, Wagerer S, Saffrich R, Mertens D, Ansorge W, Hoffmann I . The CDC25B phosphatase is essential for the G2/M phase transition in human cells. J Cell Sci 1998; 111: 2445–53.
Gabrielli BG, De Souza CP, Tonks ID, Clark JM, Hayward NK, El-lem KA . Cytoplasmic accumulation of CDC25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells. J Cell Sci 1996; 109: 1081–93.
Hoffman I, Draetta I, Karsenti G . Activation of the phosphatase activity of human CDC25 A by a CDK2-cyclin E dependent phosphorylation at the Gl/S transition. EMBO J 1994; 13: 4302–10.
Jinno S, Suto K, Nagata A, Igarashi M, Kanaoka Y, Nojima H, et al. CDC25A is a novel phosphatase functioning early in the cell cycle. EMBO J 1994; 13: 1549–56.
Boutros R, Lobjois V, Ducommun B . CDC25 phosphatases in cancer cells: key players? Good targets? Nature Reviews Cancer 2005; 7: 495–507.
Kar S, Wang M, Ham SW, Carr BI . H32, a nonquinone sulfone analog of vitamin K3, inhibits human hepatoma cell growth by inhibiting Cdc25 and activating ERK. Cancer Biol Ther 2006; 5: 1340–7.
Wrobel J, Sredy J, Moxham C, Dietrich A, Li Z, Sawicki DR, et al. PTP 1B inhibition and antihyperglycemic activity in the ob/ob mouse model of novel ll-arylbenzo[b]naphtho[2, 3-d]furans and ll-arylbenzo[b]naphtho[2, 3-d]thiophenes. J Med Chem 1999; 42: 3199–202.
Cheon HG, Kim SM, Yang SD, Ha JD, Choi JK . Discovery of a novel protein tyrosine phosphatase-IB inhibitor, KR61639: potential development as an antihyperglycemic agent. Eur J Pharmacol 2004; 485: 333–9.
Shi L, Yu HP, Zhou YY, Du JQ, Shen Q, Li JY, et al. Discovery of a novel competitive inhibitor of PTP1B by high-throughput screening. Acta Pharmacol Sin 2008; 29: 278–84.
Brezak MC, Quaranta M, Contour-Galcera MO, Lavergne O, Mondesert O, Auvray P, et al. Inhibition of human tumor cell growth in vivo by an orally bioavailable inhibitor of CDC25 phosphatases. Mol Cancer Ther 2005; 4: 1378–87.
Brisson M, Nguyen T, Vogt A, Yalowich J, Giorgianni A, Tobi D, et al. Discovery and characterization of novel small molecule inhibitors of human CDC25B dual specificity phosphatase. Mol Pharmacol 2004; 66: 824–33.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Project supported by the Hi-Tech Research and Development Program of China grant (No 2006AA02Z315).
Rights and permissions
About this article
Cite this article
Feng, X., Wang, Ln., Zhou, Yy. et al. Discovery and characterization of a novel inhibitor of CDC25B, LGH00045. Acta Pharmacol Sin 29, 1268–1274 (2008). https://doi.org/10.1111/j.1745-7254.2008.00841.x
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1111/j.1745-7254.2008.00841.x
Keywords
This article is cited by
-
Potent CDC25B and PTP1B phosphatase inhibitors: 2′,4′,6′-trihydroxylchalcone derivatives
Medicinal Chemistry Research (2015)
-
Discovery of potent inhibitors for phosphodiesterase 5 by virtual screening and pharmacophore analysis
Acta Pharmacologica Sinica (2009)
-
LGH00031, a novel ortho-quinonoid inhibitor of cell division cycle 25B, inhibits human cancer cells via ROS generation
Acta Pharmacologica Sinica (2009)