Carbonic anhydrase IX: A new drug target for designing diagnostic tools and antitumor agents

The tumor associated metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isozyme CA IX is highly overexpressed in many cancer types by the hypoxia inducible factor-1a (HIF-1a) cascade. Many hypoxic tumors overexpress CA IX and show a bad response to classical chemo- and radiotherapies. CA IX significantly contributes to acidification of the tumor environment, by catalyzing the hydration of carbon dioxide to bicarbonate and protons with its extracellularly situated active site. This leads to the acquisition of metastasic phenotypes and chemoresistance with many anticancer drugs. The report of the X-ray crystal structure of CA IX, which is a dimeric protein with a quaternary structure not evidenced earlier for this family of enzymes, allows for structure-based drug design campaigns of inhibitors against this novel antitumor target. Indeed, it has been known for some time that aromatic/heterocyclic sulfonamides and sulfamates have good affinity for this isoform, but generally they do not show specificity for the inhibition of the tumor-associated isoform versus the remaining CA isozymes (CA I-VII, and XII-XV) found in mammals. Inhibition of CA IX by specific and potent sulfonamide inhibitors was shown to revert the tumor acidification processes, establishing a clear-cut role of CA IX in tumorigenesis. The development of a wide range of such inhibitors belonging to diverse chemical classes (sulfonamides, sulfamates, sulfamides), such as membrane-impermeant, fluorescent or metal-containing compounds, provides useful tools for highlighting the exact role of CA IX in hypoxic cancers, to control the pH (im)balance of tumor cells, and to develop novel diagnostic or therapeutic applications for the management of tumors. Work from several laboratories recently reported the proof-of-concept studies for the use of CA IX inhibitors as well as antibodies both in the therapy and imaging of hypoxic tumors.

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1. Supuran, C. T. Nat. Rev. Drug Discov. 2008, 7, 168-181.
2. Supuran, C. T.; Scozzafava, A.; Conway, J. Carbonic Anhydrase - Its Inhibitors and Activators. CRC Press: Boca Raton, New York, London, 2004; pp 1-363.
3. Pastorekova, S.; Zatovicova, M.; Pastorek, J. Curr. Pharm. Des. 2008,14, 685-98.
4. Parkkila, S. BJU Int. 2008, 101 Suppl 4, 16-21.
5. Scozzafava, A.; Mastrolorenzo, A.; Supuran, C.T. Expert Opin. Ther. Pat. 2004, 14, 667-702.
6. Pastorekova, S.; Kopacek, J.; .; Pastorek, J. Curr. Top. Med. Chem. 2007, 7, 893-899.
7. Scozzafava, A.; Mastrolorenzo, A.; Supuran, C. T. Expert Opin. Ther. Pat. 2006, 16, 1627-1664.
8. Hilvo, M.; Baranauskiene, L.; Salzano, A.M.; Scaloni, A.; Matulis, D.; Innocenti, A.; Scozzafava, A.; Monti, S.M.; Di Fiore, A.; De Simone, G.; Lindfors, M.; Janis, J.; Valjakka, J.; Pastorekova, S.; Pastorek, J.; Kulomaa, M.S.; Nordlund, H.R.; Supuran, C.T.; Parkkila, S. J. Biol. Chem. 2008, 283, 27799-27809.
9. Supuran, C. T.; Scozzafava, A. Expert Opin. Ther. Pat.2002, 12, 217 - 242.
10. Supuran, C. T.; Scozzafava, A.; Casini, A. Med. Res.Rev. 2003, 23, 146-189.
11. Kivelä, A.J.; Parkkila, S.; Saarnio, J.; Karttunen, T.J.; Kivelä, J.; Parkkila A.K.; Pastoreková, S.; Pastorek, J.; Waheed, A.; Sly, W.S.; Rajaniemi, H. Histochem. Cell Biol. 2000, 114, 197-204.
12. Wykoff, C.C.; Beasley, N.J.; Watson, P.H.; Turner, K.J.; Pastorek, J.; Sibtain, A.; Wilson, G.D.; Turley, H.; Talks, K.L.; Maxwell, .P.H.; Pugh, C.W.; Ratcliffe, P.J.; Harris, A.L. Cancer Res. 2000, 60, 7075-7083.
13. Brahimi-Horn, M.C.; Pouysségur, J. Essays Biochem. 2007, 43, 165-178
14. Bartosova, M.; Parkkila, S.; Pohlodek, K.; Karttunen, T.J.; Galbavy, S.; Mucha, V.; Harris, A.L.; Pastorek, J.; Pastorekova, S. J. Pathol. 2002, 197, 1-8.
15. Kaelin, W.G. Jr.; Ratcliffe, P.J. Mol. Cell. 2008, 30, 393- 402.
16. Švastová, E.; Huliková, A.; Rafajová, M.; Zat’ovičová, M.; Gibadulinová, A.; Casini, A.; Cecchi, A.; Scozzafava, A.; Supuran, C.; Pastorek, J. FEBS Letters. 2004, 577, 439- 445.
17. Alterio, V.; Hilvo, M.; Di Fiore, A.; Supuran, C.T.; Pan, P.; Parkkila, S.; Scaloni, A.; Pastorek, J.; Pastorekova, S.; Pedone, C.; Scozzafava, A.; Monti, S.M.; De Simone, G. Proc. Natl. Acad. Sci. USA, 2009, 106, 16233 – 16238
18. Innocenti, A.; Pastorekova, S.; Pastorek, J.; Scozzafava, A.; De Simone, G.; Supuran, C.T. Bioorg. Med. Chem. Lett. 2009, 19, 5825-5828
19. Supuran, C.T.; Briganti, F.; Tilli, S.; Chegwidden, W.R.; Scozzafava, A. Bioorg. Med. Chem. 2001, 9, 703-714.
20. Swietach, P.; Wigfield, S.; Cobden, P.; Supuran, C.T.; Harris, A.L.; Vaughan-Jones, R.D. J Biol. Chem. 2008, 283, 20473-83.
21. Pastorekova, S.; Casini, A.; Scozzafava, A.; Vullo, D.; Pastorek, J.; Supuran, C.T. Bioorg. Med. Chem. Lett. 2004, 14, 869–873.
22. Swietach, P.; Wigfield, S.; Supuran, C.T.; Harris, A.L.; Vaughan-Jones, R.D. BJU Int. 2008, 101 Suppl 4, 22-24.
23. Supuran, C.T. Expert Opin. Investig. Drugs 2003, 12, 283- 287.
24. Cecchi, A.; Hulikova, A.; Pastorek, J.; Pastoreková, S.; Scozzafava, A.; Winum, J.-Y.; Montero, J.-L.; Supuran, C.T. J. Med. Chem. 2005, 48, 4834-4841.
25. Thiry, A.; Dogné, J.-M.; Masereel, B.; Supuran C.T. Trends Pharmacol. Sci. 2006, 27, 566–573.
26. Dubois, L.; Douma, K.; Supuran, C.T.; Chiu, R.K.; van Zandvoort, M.A.M.J.; Pastoreková, S.; Scozzafava, A.; Wouters, B.G.; Lambin, P. Radiother. Oncol. 2007, 83, 367–373.
27. Winum, J.Y.; Rami, M.; Scozzafava, A.; Montero, J.L.; Supuran, C. Med. Res. Rev. 2008, 28, 445-63.
28. Özensoy, O.; Puccetti, L.; Fasolis, G.; Arslan, O.; Scozzafava, A.; Supuran, C.T. Bioorg. Med. Chem. Lett. 2005, 15, 4862-4866.
29. Wilkinson, B.L.; Bornaghi, L.F.; Houston, T.A.; Innocenti, A.; Supuran, C.T.; Poulsen, S.-A. J. Med. Chem. 2006, 49, 6539-6548
30. Supuran, C.T.; Scozzafava, A. Bioorg. Med. Chem. 2007, 15, 4336-4350.
31. Ilies, M.A.; Vullo, D.; Pastorek, J.; Scozzafava, A.; Ilies, M.; Caproiu, M.T.; Pastorekova, S.; Supuran, C.T. J. Med. Chem. 2003, 46, 2187-2196.
32. Winum, J.-Y.; Vullo, D.; Casini, A.; Montero, J.-L.; Scozzafava, A.; Supuran, C.T. J. Med. Chem. 2003, 46, 2197-2204.
33. Vullo, D.; Innocenti, A.; Nishimori, I.; Pastorek, J.; Scozzafava, A.; Pastorekova, S.; Supuran, C.T. Bioorg. Med. Chem. Lett. 2005, 15, 963-969.
34. Pastorekova, S.; Vullo, D.; Casini, A.; Scozzafava, A.; Pastorek, J.; Nishimori, I.; Supuran, C.T. J. Enz. Inhib. Med. Chem. 2005, 20, 211-217
35. Di Fiore, A.; De Simone, G.; Menchise, V.; Pedone, C.; Casini, A.; Scozzafava, A.; Supuran, C.T. Bioorg. Med. Chem. Lett. 2005, 15, 1937-1942
36. Menchise, V.; De Simone, G.; Alterio, V.; Di Fiore, A.; Pedone, C.; Scozzafava, A.; Supuran, C.T. J. Med. Chem. 2005, 48, 5721-5727.
37. Alterio, V.; Vitale, R. M.; Monti, S. M.; Pedone, C.; Scozzafava, A.; Cecchi, A.; De Simone, G.; Supuran, C. T. J. Am. Chem. Soc. 2006, 128, 8329-8335.
38. Garaj, V.; Pucetti, L.; Fasolis, G.; Winum, J.-Y.; Montero, J.-L.; Scozzafava, A.; Vullo, D.; Innocenti, A.; Supuran, C.T. Bioorg. Med. Chem. Lett. 2004, 14, 5427-5433.
39. Supuran, C.T. BJU International 2008, 101, 39-40.
40. Maresca, A.; Temperini, C.; Vu, H.; Pham, N.B.; Poulsen, S.A.; Scozzafava, A.; Quinn, R.J.; Supuran, C.T. J. Am. Chem. Soc. 2009, 131, 3057-3062.
41. Maresca, A.; Temperini, C.; Pochet, L.; Masereel, B.; Scozzafava, A.; Supuran, C.T. J. Med Chem. 2009, in press.
42. Parkkila, S.; Innocenti, A.; Kallio, H.; Hilvo, M.; Scozzafava, A.; Supuran, C.T. Bioorg. Med. Chem. Lett. 2009, 19, 4102-4106.
43. Dubois, L.; Lieuwes, N.G.; Maresca, A.; Thiry, A.; Supuran, C.T.; Scozzafava, A.; Wouters, B.G.; Lambin, P. Radiother. Oncol. 2009, 92, 423-428.
44. De Simone, G.; Vitale, R.M.; Di Fiore, A.; Pedone, C.; Scozzafava, A.; Montero, J.L.; Winum, J.Y.; Supuran, C.T. J. Med. Chem. 2006, 49, 5544-5551.
45. Wilkinson, B.L.; Bornaghi, L.F.; Houston, T.A.; Innocenti, A.; Vullo, D.; Supuran, C.T. S.A. Poulsen, J. Med. Chem. 2007, 50, 1651-1657.
46. Winum, J.Y.; Temperini, C.; El Cheikh, K.; Innocenti, A.; Vullo, D.; Ciattini, S.; Montero, J.L.; Scozzafava, A.; Supuran, C.T. J. Med. Chem. 2006, 49, 7024-7031.
47. Colinas, P.A.; Bravo, R.D.; Vullo, D.; Scozzafava, A.; Supuran, C.T. Bioorg. Med. Chem. Lett. 2007, 17, 5086- 5090.
48. Innocenti, A.; Vullo, D.; Scozzafava, A.; Supuran, C.T. Bioorg. Med. Chem. Lett. 2008, 18, 1583-1587.
49. Innocenti, A.; Vullo, D.; Scozzafava, A.; Supuran, C.T. Bioorg. Med. Chem. 2008, 16, 7424-7428.
50. Bayram, E.; Senturk, M.; Kufrevioglu, O.I.; Supuran, C.T. Bioorg. Med. Chem. 2008, 16, 9101-9105.
51. Chiche, J.; Ilc, K.; Laferrière, J.; Trottier, E.; Dayan, F.; Mazure, N.M.; Brahimi-Horn, M.C.; Pouysségur, J. Cancer Res.. 2009, 69, 358-368.
52. Ahlskog, J.K.J.; Dumelin, C.E.; Trüssel, S.; Marlind, J.; Neri, D. Bioorg. Med. Chem. Lett. 2009, 19, 4851-4856.
53. Ahlskog, J.K.; Schliemann, C.; Mårlind, J.; Qureshi, U.; Ammar, A.; Pedleym R.B.; Neri, D. Br. J. Cancer. 2009, 101, 645-657.