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Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties.

Genis C, Sippel KH, Case N, Cao W, Avvaru BS, Tartaglia LJ, Govindasamy L, Tu C, Agbandje-McKenna M, Silverman DN, Rosser CJ, McKenna R
Biochemistry 48 1322-31 (2009)
Related entries: 3d8w, 3d9z, 3daz, 3dc3, 3dc9, 3dcc, 3dcs, 3dcw, 3dd0

Cited: 32 times
EuropePMC logo PMID: 19170619

Abstract

Recently, a convincing body of evidence has accumulated suggesting that the overexpression of carbonic anhydrase isozyme IX (CA IX) in some cancers contributes to the acidification of the extracellular matrix, which in turn promotes the growth and metastasis of the tumor. These observations have made CA IX an attractive drug target for the selective treatment of certain cancers. Currently, there is no available X-ray crystal structure of CA IX, and this lack of availability has hampered the rational design of selective CA IX inhibitors. In light of these observations and on the basis of structural alignment homology, using the crystal structure of carbonic anhydrase II (CA II) and the sequence of CA IX, a double mutant of CA II with Ala65 replaced by Ser and Asn67 replaced by Gln has been constructed to resemble the active site of CA IX. This CA IX mimic has been characterized kinetically using (18)O-exchange and structurally using X-ray crystallography, alone and in complex with five CA sulfonamide-based inhibitors (acetazolamide, benzolamide, chlorzolamide, ethoxzolamide, and methazolamide), and compared to CA II. This structural information has been evaluated by both inhibition studies and in vitro cytotoxicity assays and shows a correlated structure-activity relationship. Kinetic and structural studies of CA II and CA IX mimic reveal chlorzolamide to be a more potent inhibitor of CA IX, inducing an active-site conformational change upon binding. Additionally, chlorzolamide appears to be cytotoxic to prostate cancer cells. This preliminary study demonstrates that the CA IX mimic may provide a useful model to design more isozyme-specific CA IX inhibitors, which may lead to development of new therapeutic treatments of some cancers.

Articles - 3dbu mentioned but not cited (2)

  1. Design of a carbonic anhydrase IX active-site mimic to screen inhibitors for possible anticancer properties. Genis C, Sippel KH, Case N, Cao W, Avvaru BS, Tartaglia LJ, Govindasamy L, Tu C, Agbandje-McKenna M, Silverman DN, Rosser CJ, McKenna R. Biochemistry 48 1322-1331 (2009)
  2. Development of a Fingerprint-Based Scoring Function for the Prediction of the Binding Mode of Carbonic Anhydrase II Inhibitors. Poli G, Jha V, Martinelli A, Supuran CT, Tuccinardi T. Int J Mol Sci 19 E1851 (2018)


Reviews citing this publication (2)

  1. Cancer Drug Development of Carbonic Anhydrase Inhibitors beyond the Active Site. Singh S, Lomelino CL, Mboge MY, Frost SC, McKenna R. Molecules 23 E1045 (2018)
  2. Thermodynamic, kinetic, and structural parameterization of human carbonic anhydrase interactions toward enhanced inhibitor design. Linkuvienė V, Zubrienė A, Manakova E, Petrauskas V, Baranauskienė L, Zakšauskas A, Smirnov A, Gražulis S, Ladbury JE, Matulis D. Q Rev Biophys 51 e10 (2018)

Articles citing this publication (28)

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  4. Saccharin: a lead compound for structure-based drug design of carbonic anhydrase IX inhibitors. Mahon BP, Hendon AM, Driscoll JM, Rankin GM, Poulsen SA, Supuran CT, McKenna R. Bioorg Med Chem 23 849-854 (2015)
  5. Structural insights into carbonic anhydrase IX isoform specificity of carbohydrate-based sulfamates. Moeker J, Mahon BP, Bornaghi LF, Vullo D, Supuran CT, McKenna R, Poulsen SA. J Med Chem 57 8635-8645 (2014)
  6. In vitro evaluation of ESE-15-ol, an estradiol analogue with nanomolar antimitotic and carbonic anhydrase inhibitory activity. Stander BA, Joubert F, Tu C, Sippel KH, McKenna R, Joubert AM. PLoS One 7 e52205 (2012)
  7. Structure activity study of carbonic anhydrase IX: Selective inhibition with ureido-substituted benzenesulfonamides. Mboge MY, Mahon BP, Lamas N, Socorro L, Carta F, Supuran CT, Frost SC, McKenna R. Eur J Med Chem 132 184-191 (2017)
  8. Structure-Activity Relationships of Benzenesulfonamide-Based Inhibitors towards Carbonic Anhydrase Isoform Specificity. Bhatt A, Mahon BP, Cruzeiro VW, Cornelio B, Laronze-Cochard M, Ceruso M, Sapi J, Rance GA, Khlobystov AN, Fontana A, Roitberg A, Supuran CT, McKenna R. Chembiochem 18 213-222 (2017)
  9. Signaling pathways of ESE-16, an antimitotic and anticarbonic anhydrase estradiol analog, in breast cancer cells. Stander BA, Joubert F, Tu C, Sippel KH, McKenna R, Joubert AM. PLoS One 8 e53853 (2013)
  10. Novel estradiol analogue induces apoptosis and autophagy in esophageal carcinoma cells. Wolmarans E, Mqoco TV, Stander A, Nkandeu SD, Sippel K, McKenna R, Joubert A. Cell Mol Biol Lett 19 98-115 (2014)
  11. A sucrose-binding site provides a lead towards an isoform-specific inhibitor of the cancer-associated enzyme carbonic anhydrase IX. Pinard MA, Aggarwal M, Mahon BP, Tu C, McKenna R. Acta Crystallogr F Struct Biol Commun 71 1352-1358 (2015)
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  13. Inhibition of Carbonic Anhydrase Using SLC-149: Support for a Noncatalytic Function of CAIX in Breast Cancer. Mboge MY, Combs J, Singh S, Andring J, Wolff A, Tu C, Zhang Z, McKenna R, Frost SC. J Med Chem 64 1713-1724 (2021)
  14. Synthesis, biological activity and multiscale molecular modeling studies for coumaryl-carboxamide derivatives as selective carbonic anhydrase IX inhibitors. Zengin Kurt B, Sonmez F, Durdagi S, Aksoydan B, Ekhteiari Salmas R, Angeli A, Kucukislamoglu M, Supuran CT. J Enzyme Inhib Med Chem 32 1042-1052 (2017)
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  16. Chalcogen Bond as a Factor Stabilizing Ligand Conformation in the Binding Pocket of Carbonic Anhydrase IX Receptor Mimic. Wojtkowiak K, Michalczyk M, Zierkiewicz W, Jezierska A, Panek JJ. Int J Mol Sci 23 13701 (2022)
  17. Induction of the intrinsic apoptotic pathway via a new antimitotic agent in an esophageal carcinoma cell line. Wolmarans E, Sippel K, McKenna R, Joubert A. Cell Biosci 4 68 (2014)
  18. Mutation of Phe91 to Asn in human carbonic anhydrase I unexpectedly enhanced both catalytic activity and affinity for sulfonamide inhibitors. Kockar F, Maresca A, Aydin M, Işik S, Turkoglu S, Sinan S, Arslan O, Güler OO, Turan Y, Supuran CT. Bioorg Med Chem 18 5498-5503 (2010)
  19. Ultrastructural changes of erythrocytes in whole blood after exposure to prospective in silico-designed anticancer agents: a qualitative case study. Repsold L, Mqoco T, Wolmarans E, Nkandeu S, Theron J, Piorkowski T, Toit Pd, Papendorp Dv, Joubert AM. Biol Res 47 39 (2014)
  20. Engineered Carbonic Anhydrase VI-Mimic Enzyme Switched the Structure and Affinities of Inhibitors. Kazokaitė J, Kairys V, Smirnovienė J, Smirnov A, Manakova E, Tolvanen M, Parkkila S, Matulis D. Sci Rep 9 12710 (2019)
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  22. Synthesis, Biological Evaluation, and Molecular Docking of Novel Thiazoles and [1,3,4]Thiadiazoles Incorporating Sulfonamide Group as DHFR Inhibitors. Riyadh SM, El-Motairi SA, Ahmed HEA, Khalil KD, Habib EE. Chem Biodivers 15 e1800231 (2018)
  23. Autophagy induced by a sulphamoylated estrone analogue contributes to its cytotoxic effect on breast cancer cells. Verwey M, Nolte EM, Joubert AM, Theron AE. Cancer Cell Int 16 91 (2016)
  24. Mutation of active site residues Asn67 to Ile, Gln92 to Val and Leu204 to Ser in human carbonic anhydrase II: influences on the catalytic activity and affinity for inhibitors. Turkoglu S, Maresca A, Alper M, Kockar F, Işık S, Sinan S, Ozensoy O, Arslan O, Supuran CT. Bioorg Med Chem 20 2208-2213 (2012)
  25. New Insights into Conformationally Restricted Carbonic Anhydrase Inhibitors. Combs J, Bozdag M, Cravey LD, Kota A, McKenna R, Angeli A, Carta F, Supuran CT. Molecules 28 890 (2023)
  26. Green Synthesis of Oxoquinoline-1(2H)-Carboxamide as Antiproliferative and Antioxidant Agents: An Experimental and In-Silico Approach to High Altitude Related Disorders. Ali A, Ali A, Warsi MH, Rahman MA, Ahsan MJ, Azam F. Molecules 27 309 (2022)
  27. In silico prediction suggests inhibitory effect of halogenated boroxine on human catalase and carbonic anhydrase. Corbo T, Kalajdzic A, Delic D, Suleiman S, Pojskic N. J Genet Eng Biotechnol 20 153 (2022)
  28. Kinetic Study of CO2 Hydration by Small-Molecule Catalysts with A Second Coordination Sphere that Mimic the Effect of the Thr-199 Residue of Carbonic Anhydrase. Park D, Lee MS. Biomimetics (Basel) 4 E66 (2019)


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