Structural basis of serine/threonine phosphatase inhibition by the archetypal small molecules cantharidin and norcantharidin

Journal of Medicinal Chemistry

Volumn 52, Issue 15, 2009, Pages 4838-4843

  Bertini, I ^a   Calderone, V ^a   Fragai, M ^a   Luchinat, C ^a   Talluri, E ^a  

^a UNIVERSITY OF FLORENCE   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CANTHARIDIN; DICARBOXYLIC ACID DERIVATIVE; LIGAND; NORCANTHARIDIN; PHOSPHATASE; SERINE THREONINE PHOSPHATASE; SERINE THREONINE PHOSPHATASE 5; UNCLASSIFIED DRUG;

ARTICLE; COMPLEX FORMATION; CRYSTAL STRUCTURE; DRUG CONFORMATION; DRUG CYTOTOXICITY; DRUG DESIGN; ENZYME ACTIVE SITE; ENZYME INHIBITION; HYDROLYSIS; STRUCTURE ACTIVITY RELATION; TUMOR CELL;

BICYCLO COMPOUNDS, HETEROCYCLIC; BINDING SITES; CANTHARIDIN; ENZYME INHIBITORS; HYDROPHOBICITY; PHOSPHOPROTEIN PHOSPHATASES; PROTEIN CONFORMATION; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 68549115381     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm900610k     Document Type: Article

References (55)

1. Li, Y. M.; Casida, J. E. Cantharidin-Binding Protein - Identification As Protein Phosphatase-2 A. Proc. Natl. Acad. Sci. U.S.A. 1992, 89, 11867-11870.
2. Chen, Y. N.; Chen, J. C.; Yin, S. C.; Wang, G. S.; Tsauer, W.; Hsu, S. F.; Hsu, S. L. Effector mechanisms of norcantharidin-induced mitotic arrest and apoptosis in human hepatoma cells. Int. J. Cancer 2002, 100, 158-165.
3. Efferth, T.; Rauh, R.; Kahl, S.; Tomicic, M.; Bochzelt, H.; Tome, M. E.; Briehl, M. M.; Bauer, R.; Kaina, B. Molecular modes of action of cantharidin in tumor cells. Biochem. Pharmacol. 2005, 69, 811-818.
4. Rauh, R.; Kahl, S.; Boechzelt, H.; Bauer, R.; Kaina, B.; Efferth, T. Molecular biology of cantharidin in cancer cells. Chin. Med. 2007, 2, 8.
5. Dorn, D. C.; Kou, C. A.; Png, K. J.; and Moore, M. A. The effect of cantharidins on leukemic stem cells. Int. J. Cancer 2008.
6. Chen, Y. N.; Cheng, C. C.; Chen, J. C.; Tsauer, W.; Hsu, S. L. Norcantharidin-induced apoptosis is via the extracellular signalregulated kinase and c-Jun-NH2-terminal kinase signaling pathways in human hepatoma HepG2 cells. Br. J. Pharmacol. 2003, 140, 461-470.
7. Sagawa, M.; Nakazato, T.; Uchida, H.; Ikeda, Y.; Kizaki, M. Cantharidin induces apoptosis of human multiple myeloma cells via inhibition of the JAK/STAT pathway. Cancer Sci. 2008, 99, 1820-1826.
8. Kok, S. H.; Cheng, S. J.; Hong, C. Y.; Lee, J. J.; Lin, S. K.; Kuo, Y. S.; Chiang, C. P.; Kuo, M. Y. Norcantharidin-induced apoptosis in oral cancer cells is associated with an increase of proapoptotic to antiapoptotic protein ratio. Cancer Lett. 2005, 217, 43-52.
9. Hill, T. A.; Stewart, S. G.; Gordon, C. P.; Ackland, S. P.; Gilbert, J.; Sauer, B.; Sakoff, J. A.; McCluskey, A. Norcantharidin analogues: synthesis, anticancer activity and protein phosphatase 1 and 2A inhibition. ChemMedChem 2008, 3, 1878-1892.
10. Norbury, C. J.; Zhivotovsky, B. DNA damage-induced apoptosis. Oncogene 2004, 23, 2797-2808.
11. Slee, E. A.; O'Connor, D. J.; Lu, X. To die or not to die: how does p53 decide?. Oncogene 2004, 23, 2809-2818.
12. Babine, R. E.; Bender, S. L. Molecular Recognition of Protein-Ligand Complexes: Applications to Drug Design. Chem. Rev. 1997, 97, 1359-1472.
13. Aureli, L.; Gioia, M.; Cerbara, I.; Monaco, S.; Fasciglione, G. F.; Marini, S.; Ascenzi, P.; Topai, A.; Coletta, M. Structural bases for substrate and inhibitor recognition by matrix metalloproteinases. Curr. Med. Chem. 2008, 15, 2192-2222.
14. Knapp, J.; Boknik, P.; Huke, S.; Gombosova, I.; Linck, B.; Luss, H.; Muller, F. U.; Muller, T.; Nacke, P.; Schmitz, W.; Vahlensieck, U.; Neumann, J. Contractility and inhibition of protein phosphatases by cantharidin. Gen. Pharmacol. 1998, 31, 729-733.
15. McCluskey, A.; Sakoff, J. A. Small molecule inhibitors of serine/ threonine protein phosphatases. Mini. Rev. Med. Chem. 2001, 1, 43-55.
16. Melnikova, I.; Golden, J. Targeting protein kinases. Nat. Rev. Drug Discovery 2004, 3, 993-994.
17. Ventura, J. J.; Nebreda, A. R. Protein kinases and phosphatases as therapeutic targets in cancer. Clin. Transl. Oncol. 2006, 8, 153-160.
18. Sawyer, T. K.; Shakespeare, W. C.; Wang, Y.; Sundaramoorthi, R.; Huang, W. S.; Metcalf, C. A. III; Thomas, M.; Lawrence, B. M.; Rozamus, L.; Noehre, J.; Zhu, X.; Narula, S.; Bohacek, R. S.; Weigele, M.; Dalgarno, D. C. Protein phosphorylation and signal transduction modulation: chemistry perspectives for small-molecule drug discovery. Med. Chem. 2005, 1, 293-319.
19. Vazquez, J.; Tautz, L.; Ryan, J. J.; Vuori, K.; Mustelin, T.; Pellecchia, M. Development of Molecular Probes for Second-Site Screening and Design of Protein Tyrosine Phosphatase Inhibitors. J. Med. Chem. 2007, 50, 2137-2143.
20. Barford, D.; Das, A. K.; Egloff, M. P. The structure and mechanism of protein phosphatases: insights into catalysis and regulation. Annu. Rev. Biophys. Biomol. Struct. 1998, 27, 133-164.
21. Hinds, T. D. Jr.; Sanchez, E. R. Protein phosphatase 5. Int. J. Biochem. Cell Biol. 2008, 40, 2358-2362.
22. Kennelly, P. J. Protein phosphatases;a phylogenetic perspective. Chem. Rev. 2001, 101, 2291-2312.
23. McConnell, J. L.; Wadzinski, B. E. Targeting protein serine/ threonine phosphatases for drug development. Mol. Pharmacol. 2009, 75, 1249-1261.
24. Barton, G. J.; Cohen, P. T. W.; Barford, D. Conservation Analysis and Structure Prediction of the Protein Serine/Threonine Phosphatases; Sequence Similarity with Diadenosine Tetraphosphatase from Escherichia coli Suggests Homology to the Protein Phosphatases. Eur. J. Biochem. 1994, 220, 225-237.
25. Barford, D. Molecular mechanisms of the protein serine threonine phosphatases. Trends Biochem. Sci. 1996, 21, 407-412.
26. Chen, M. X.; McPartlin, A. E.; Brown, L.; Chen, Y. H.; Barker, H. M.; Cohen, P. T. W. A Novel Human Protein Serine/Threonine Phosphatase, Which Possesses 4 Tetratricopeptide Repeat Motifs and Localizes to the Nucleus. EMBO J. 1994, 13, 4278-4290.
27. McCluskey, A.; Sim, A. T.; Sakoff, J. A. Serine-threonine protein phosphatase inhibitors: development of potential therapeutic strategies. J. Med. Chem. 2002, 45, 1151-1175.
28. Yang, J.; Roe, S. M.; Cliff, M. J.; Williams, M. A.; Ladbury, J. E.; Cohen, P. T. W.; Barford, D. Molecular basis for TPR domainmediated regulation of protein phosphatase. EMBO J. 2005, 24, 1-10.
29. Swingle, M. R.; Honkanen, R. E.; Ciszak, E. M. Structural basis for the catalytic activity of human serine/threonine protein phosphatase-5. J. Biol. Chem. 2004, 279, 33992-33999.
30. Kelker, M. S.; Page, R.; Peti, W. Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-based drug design of serine/threonine phosphatase inhibitors. J. Mol. Biol. 2009, 385, 11-21.
31. Maynes, J. T.; Luu, H. A.; Cherney, M. M.; Andersen, R. J.; Williams, D.; Holmes, C. F.; James, M. N. Crystal structures of protein phosphatase-1 bound to motuporin and dihydromicrocystin-LA: elucidation of the mechanism of enzyme inhibition by cyanobacterial toxins. J. Mol. Biol. 2006, 356, 111-120.
32. Xing, Y.; Xu, Y.; Chen, Y.; Jeffrey, P. D.; Chao, Y.; Lin, Z.; Li, Z.; Strack, S.; Stock, J. B.; Shi, Y. Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell 2006, 127, 341-353.
33. Li, H.; Zhang, L.; Rao, A.; Harrison, S. C.; Hogan, P. G. Structure of calcineurin in complex with PVIVIT peptide: portrait of a lowaffinity signalling interaction. J. Mol. Biol. 2007, 369, 1296-1306.
34. Swingle, M.; Ni, L.; Honkanen, R. E. Small-molecule inhibitors of Ser/Thr protein phosphatases: specificity, use and common forms of abuse. Methods Mol. Biol. 2007, 365, 23-38.
35. Maynes, J. T.; Bateman, K. S.; Cherney, M. M.; Das, A. K.; Luu, H. A.; Holmes, C. F.; James, M. N. Crystal structure of the tumorpromoter okadaic acid bound to protein phosphatase-1. J. Biol. Chem. 2001, 276, 44078-44082.
36. Maynes, J. T.; Perreault, K. R.; Cherney, M. M.; Luu, H. A.; James, M. N.; Holmes, C. F. Crystal structure and mutagenesis of a protein phosphatase-1:calcineurin hybrid elucidate the role of the beta12-beta13 loop in inhibitor binding. J. Biol. Chem. 2004, 279, 43198-43206.
37. Xing, Y.; Xu, Y.; Chen, Y.; Jeffrey, P. D.; Chao, Y.; Lin, Z.; Li, Z.; Strack, S.; Stock, J. B.; Shi, Y. Structure of protein phosphatase 2A core enzyme bound to tumor-inducing toxins. Cell 2006, 127, 341-353.
38. Kita, A.; Matsunaga, S.; Takai, A.; Kataiwa, H.; Wakimoto, T.; Fusetani, N.; Isobe, M.; Miki, K. Crystal structure of the complex between calyculin A and the catalytic subunit of protein phosphatase 1. Structure 2002, 10, 715-724.
39. Baba, Y.; Hirukawa, N.; Tanohira, N.; Sodeoka, M. Structurebased design of a highly selective catalytic site-directed inhibitor of Ser/Thr protein phosphatase 2B (calcineurin). J. Am. Chem. Soc. 2003, 125, 9740-9749.
40. McCluskey, A.; Keane, M. A.; Mudgee, L. M.; Sim, A. T. R.; Sakoff, J.; Quinn, R. J. Anhydride modified cantharidin analogues. Is ring opening important in the inhibition of protein phosphatase 2A?. Eur. J. Med. Chem. 2000, 35, 957-964.
41. Gauss, C. M.; Sheppeck, J. E.; Nairn, A. C.; Chamberlin, R. A molecular modeling analysis of the binding interactions between the okadaic acid class of natural product inhibitors and the Ser-Thr phosphatases, PP1 and PP2A. Bioorg. Med. Chem. 1997, 5, 1751-1773.
42. Bertini, I.; Fragai, M.; Luchinat, C.; Talluri, E. Water-based ligand screening for paramagnetic metalloproteins. Angew. Chem., Int. Ed. 2008, 47, 4533-4537.
43. Leslie, A. G. W. Crystallographic Computing V. In Molecular Data Processing; Moras, D., Podjarny, A. D., Thierry, J.-C., Eds.; Oxford University Press: Oxford, 1991; pp 50-61.
44. Evans, P. R. Data Reduction, Proceedings of CCP4 Study Weekend. Data Collect. Process. 1993, 114-122. Conference Proceeding.
45. Rossmann, M. G.; Blow, D. M. The detection of sub-units within the crystallographic asymmetric unit. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1962, 15, 24-31.
46. Crowther, R. A. The Molecular Replacement Method. Rossmann, M. G. Ed.; Gordon & Breach: New York, 1972.
47. Vagin, A.; Teplyakov, A. MOLREP: an automated program for molecular replacement. J. Appl. Crystallogr. 1997, 30, 1022-1025.
48. Vagin, A.; Teplyakov, A. An approach to multi-copy search in molecular replacement. Acta Crystallogr., Sect. D: Biol. Crystallogr. 2000, 56, 1622-1624.
49. Murshudov, G. N.; Vagin, A. A.; Dodson, E. J. Refinement of macromolecular structures by the maximum-likelihood method. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1997, 53, 240-255.
50. McRee, D. E. XtalView: A Visual Protein Crystallographic Software System for XII/XView. J. Mol. Graphics 1992, 10, 44-47.
51. Lamzin, V. S.; Wilson, K. S. Automated refinement of protein models. Acta Crystallogr., Sect. D: Biol. Crystallogr. 1993, 49, 129-147.
52. Laskowski, R. A.; MacArthur, M. W.; Moss, D. S.; Thornton, J. M. PROCHECK: a program to check the stereochemical quality of protein structures. J. Appl. Crystallogr. 1993, 26, 283-291.
53. McCluskey, A.; Taylor, C.; Quinn, R. J.; Suganuma, M.; Fujiki, H. Inhibition of Protein Phosphatase 2A by Cantharidin. Bioorg. Med. Chem. Lett. 1996, 6, 1025-1028.
54. Baba, Y.; Hirukawa, N.; Sodeoka, M. Optically active cantharidin analogues possessing selective inhibitory activity on Ser/Thr protein phosphatase 2B (calcineurin): Implications for the binding mode. Bioorg. Med. Chem. Lett. 2005, 13, 5164-5170.
55. Sheppeck, J. E.; Gauss, C. M.; Chamberlin, A. R. Inhibition of the Ser-Thr phosphatases PP1 and PP2A by naturally occurring toxins. Bioorg. Med. Chem. 1997, 5, 1739-1750.