{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T12:08:36Z","timestamp":1791893316573,"version":"4.3.4"},"reference-count":49,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T00:00:00Z","timestamp":1575244800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100011272","name":"FP7 Health","doi-asserted-by":"publisher","award":["222741"],"award-info":[{"award-number":["222741"]}],"id":[{"id":"10.13039\/100011272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Carbonic anhydrases (CAs) are a family of enzymes involved in the pH regulation of metabolically active cells\/tissues. Upregulation of the CAIX\/XII isoforms is associated with hypoxic tumours and clinically linked with malignant progression, treatment resistance and poor prognosis. The elucidation of the crystal structure of the catalytic domains of CAIX\/XII provided the basis for the generation of CAIX\/XII selective inhibitors based on the sulfonamide, sulfamate and coumarins chemical structures. Ureido-substituted benzenesulfonamide CAIX\/XII inhibitors have shown significant potential, with U-104 (SLC-0111) currently present in clinical Phase I\/II. Ureido-substituted sulfamate CAIX\/XII inhibitors have received less attention despite encouraging preclinical test results. In triple-negative breast cancer (TNBC), ureidosulfamates revealed a significant antitumour (FC9-398A) and antimetastatic potential (S4). In small cell lung cancer (SCLC), a cancer cell type very sensitive to a dysregulation in CAIX signaling, S4 treatment was particularly effective when combined with cisplatin with no evidence of acquired cisplatin-resistance. These successful anticancer strategies should provide a solid basis for future studies on ureido-substituted sulfamates.<\/jats:p>","DOI":"10.3390\/ijms20236080","type":"journal-article","created":{"date-parts":[[2019,12,3]],"date-time":"2019-12-03T04:58:39Z","timestamp":1575349119000},"page":"6080","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX\/XII Inhibitors in the Treatment of Cancers"],"prefix":"10.3390","volume":"20","author":[{"given":"Kaye J.","family":"Williams","sequence":"first","affiliation":[{"name":"Faculty of Biology, Medicine and Health, School of Pharmacy and Optometry, University of Manchester, Manchester M13 9PL, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roben G.","family":"Gieling","sequence":"additional","affiliation":[{"name":"Faculty of Health and Life Sciences, Department of Applied Sciences, University of Northumbria, Newcastle Upon Tyne NE1 8ST, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1053\/gast.1997.v112.pm9024293","article-title":"Carbonic anhydrase IX, MN\/CA IX: Analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts","volume":"112","author":"Pastorekova","year":"1997","journal-title":"Gastroenterology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Singh, S., Lomelino, C.L., Mboge, M.Y., Frost, S.C., and McKenna, R. (2018). Cancer drug development of carbonic anhydrase inhibitors beyond the active site. Molecules, 23.","DOI":"10.3390\/molecules23051045"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1016\/j.semcancer.2014.08.002","article-title":"Hypoxia-induced carbonic anhydrase IX as a target for cancer therapy: From biology to clinical use","volume":"31","author":"Pastorek","year":"2015","journal-title":"Semin Cancer Biol"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1470","DOI":"10.1016\/j.bmc.2012.09.062","article-title":"Carbonic anhydrase IX as a target for metastatic disease","volume":"21","author":"Gieling","year":"2013","journal-title":"Bioorg. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.3892\/or.2013.2226","article-title":"Suppression of carbonic anhydrase IX leads to aberrant focal adhesion and decreased invasion of tumor cells","volume":"29","author":"Radvak","year":"2013","journal-title":"Oncol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.7314\/APJCP.2015.16.6.2187","article-title":"Cellular protrusions-lamellipodia, filopodia, invadopodia and podosomes--and their roles in progression of orofacial tumours: Current understanding","volume":"16","author":"Alblazi","year":"2015","journal-title":"Asian. Pac. J. Cancer Prev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3389\/fphys.2013.00271","article-title":"The effect of carbonic anhydrase IX on focal contacts during cell spreading and migration","volume":"4","author":"Csaderova","year":"2013","journal-title":"Front. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6244","DOI":"10.1038\/onc.2017.219","article-title":"The interactome of metabolic enzyme carbonic anhydrase IX reveals novel roles in tumor cell migration and invadopodia\/MMP14-mediated invasion","volume":"36","author":"Swayampakula","year":"2017","journal-title":"Oncogene"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.ejcb.2010.03.004","article-title":"Carbonic anhydrase XII promotes invasion and migration ability of MDA-MB-231 breast cancer cells through the p38 MAPK signaling pathway","volume":"89","author":"Hsieh","year":"2010","journal-title":"Eur. J. Cell Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"9799","DOI":"10.1002\/jcp.26947","article-title":"Inhibition of smoothened in breast cancer cells reduces CAXII expression and cell migration","volume":"233","author":"Guerrini","year":"2018","journal-title":"J. Cell. Physiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"16233","DOI":"10.1073\/pnas.0908301106","article-title":"Crystal structure of the catalytic domain of the tumor-associated human carbonic anhydrase IX","volume":"106","author":"Alterio","year":"2009","journal-title":"Proc. Natl. Acad. Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.bmcl.2010.11.064","article-title":"Inhibition of beta-carbonic anhydrases with ureido-substituted benzenesulfonamides","volume":"21","author":"Pacchiano","year":"2011","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"111600","DOI":"10.1016\/j.ejmech.2019.111600","article-title":"Carbonic anhydrase inhibitors based on sorafenib scaffold: Design, synthesis, crystallographic investigation and effects on primary breast cancer cells","volume":"182","author":"Bozdag","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"689","DOI":"10.3109\/14756366.2014.966704","article-title":"Targeting tumour hypoxia to prevent cancer metastasis. From biology, biosensing and technology to drug development: The METOXIA consortium","volume":"30","author":"Pettersen","year":"2015","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5591","DOI":"10.1021\/jm300529u","article-title":"Antimetastatic effect of sulfamate carbonic anhydrase IX inhibitors in breast carcinoma xenografts","volume":"55","author":"Gieling","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Meijer, T.W., Bussink, J., Zatovicova, M., Span, P.N., Lok, J., Supuran, C.T., and Kaanders, J.H. (2014). Tumor microenvironmental changes induced by the sulfamate carbonic anhydrase IX inhibitor S4 in a laryngeal tumor model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108068"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/ijc.31042","article-title":"Novel carbonic anhydrase IX-targeted therapy enhances the anti-tumour effects of cisplatin in small cell lung cancer","volume":"142","author":"Bryant","year":"2018","journal-title":"Int. J. Cancer."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"24856","DOI":"10.18632\/oncotarget.4498","article-title":"Evaluation of carbonic anhydrase IX as a therapeutic target for inhibition of breast cancer invasion and metastasis using a series of in vitro breast cancer models","volume":"6","author":"Ward","year":"2015","journal-title":"Oncotarget"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Vidlickova, I., Dequiedt, F., Jelenska, L., Sedlakova, O., Pastorek, M., Stuchlik, S., Pastorek, J., Zatovicova, M., and Pastorekova, S. (2016). Apoptosis-induced ectodomain shedding of hypoxia-regulated carbonic anhydrase IX from tumor cells: A double-edged response to chemotherapy. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2267-4"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"779","DOI":"10.3109\/14756366.2015.1069286","article-title":"Sulfamate inhibitor S4 influences carbonic anhydrase IX ectodomain shedding in colorectal carcinoma cells","volume":"31","author":"Hektoen","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1016\/j.bbadis.2013.01.020","article-title":"The role of proton dynamics in the development and maintenance of multidrug resistance in cancer","volume":"1832","author":"Daniel","year":"2013","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1158\/0008-5472.CAN-08-2470","article-title":"Hypoxia-inducible carbonic anhydrase IX and XII promote tumor cell growth by counteracting acidosis through the regulation of the intracellular pH","volume":"69","author":"Chiche","year":"2009","journal-title":"Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"27940","DOI":"10.18632\/oncotarget.25371","article-title":"The proteoglycan-like domain of carbonic anhydrase IX mediates non-catalytic facilitation of lactate transport in cancer cells","volume":"9","author":"Ames","year":"2018","journal-title":"Oncotarget"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Liskova, V., Hudecova, S., Lencesova, L., Iuliano, F., Sirova, M., Ondrias, K., Pastorekova, S., and Krizanova, O. (2019). Type 1 sodium calcium exchanger forms a complex with carbonic anhydrase IX and via reverse mode activity contributes to pH control in hypoxic tumors. Cancers (Basel), 11.","DOI":"10.3390\/cancers11081139"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"42857","DOI":"10.18632\/oncotarget.17143","article-title":"Inhibition of pH regulation as a therapeutic strategy in hypoxic human breast cancer cells","volume":"8","author":"Meehan","year":"2017","journal-title":"Oncotarget"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1080\/14756366.2016.1177525","article-title":"Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells","volume":"31","author":"Federici","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s11864-005-0014-1","article-title":"Combined modality therapy for limited-disease small cell lung cancer","volume":"6","author":"Raez","year":"2005","journal-title":"Curr. Treat. Options Oncol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.lungcan.2014.08.003","article-title":"Targeting hypoxia in the treatment of small cell lung cancer","volume":"86","author":"Bryant","year":"2014","journal-title":"Lung Cancer"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"360","DOI":"10.3109\/14756366.2012.736979","article-title":"Inhibition of carbonic anhydrase activity modifies the toxicity of doxorubicin and melphalan in tumour cells in vitro","volume":"28","author":"Gieling","year":"2013","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Van Kuijk, S.J., Gieling, R.G., Niemans, R., Lieuwes, N.G., Biemans, R., Telfer, B.A., Haenen, G.R., Yaromina, A., Lambin, P., and Dubois, L.J. (2016). The Sulfamate Small Molecule CAIX Inhibitor S4 Modulates Doxorubicin Efficacy. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0161040"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1021\/jm101541x","article-title":"Ureido-substituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis","volume":"54","author":"Pacchiano","year":"2011","journal-title":"J. Med. Chem."},{"key":"ref_32","first-page":"2585","article-title":"Cellular and radiobiological effects of carbonic anhydrase IX in human breast cancer cells","volume":"41","author":"Guttler","year":"2019","journal-title":"Oncol. Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3364","DOI":"10.1158\/0008-5472.CAN-10-4261","article-title":"Targeting tumor hypoxia: Suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors","volume":"71","author":"Lou","year":"2011","journal-title":"Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5210","DOI":"10.1038\/onc.2012.550","article-title":"Targeting carbonic anhydrase IX depletes breast cancer stem cells within the hypoxic niche","volume":"32","author":"Lock","year":"2013","journal-title":"Oncogene"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"191","DOI":"10.3727\/096504017X14965111926391","article-title":"Inhibition of carbonic anhydrase IX by ureidosulfonamide inhibitor U104 reduces prostate cancer cell growth, but does not modulate daunorubicin or cisplatin cytotoxicity","volume":"26","author":"Riemann","year":"2018","journal-title":"Oncol. Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1080\/14756366.2018.1532419","article-title":"The carbonic anhydrase IX inhibitor SLC-0111 sensitises cancer cells to conventional chemotherapy","volume":"34","author":"Andreucci","year":"2019","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"85861","DOI":"10.18632\/oncotarget.13040","article-title":"P-glycoprotein-mediated chemoresistance is reversed by carbonic anhydrase XII inhibitors","volume":"7","author":"Kopecka","year":"2016","journal-title":"Oncotarget"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1016\/j.bmc.2017.03.027","article-title":"Synthesis and carbonic anhydrase inhibition of a series of SLC-0111 analogs","volume":"25","author":"Carta","year":"2017","journal-title":"Bioorg. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/febs.13562","article-title":"Catalytic activity of human carbonic anhydrase isoform IX is displayed both extra- and intracellularly","volume":"283","author":"Klier","year":"2016","journal-title":"FEBS J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1007\/978-94-007-7359-2_17","article-title":"Glaucoma and the applications of carbonic anhydrase inhibitors","volume":"75","author":"Scozzafava","year":"2014","journal-title":"Subcell. Biochem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5619","DOI":"10.1016\/j.bmc.2015.07.024","article-title":"Synthesis and carbonic anhydrase I, II, IX and XII inhibitory activity of sulfamates incorporating piperazinyl-ureido moieties","volume":"23","author":"Congiu","year":"2015","journal-title":"Bioorg. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3850","DOI":"10.1016\/j.bmcl.2015.07.060","article-title":"Synthesis of sulfonamides incorporating piperazinyl-ureido moieties and their carbonic anhydrase I, II, IX and XII inhibitory activity","volume":"25","author":"Congiu","year":"2015","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"10860","DOI":"10.1021\/acs.jmedchem.8b01504","article-title":"4-Hydroxy-3-nitro-5-ureido-benzenesulfonamides Selectively Target the Tumor-Associated Carbonic Anhydrase Isoforms IX and XII Showing Hypoxia-Enhanced Antiproliferative Profiles","volume":"61","author":"Nocentini","year":"2018","journal-title":"J. Med. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1080\/14756366.2018.1524380","article-title":"Assessment of the antiproliferative and apoptotic roles of sulfonamide carbonic anhydrase IX inhibitors in HeLa cancer cell line","volume":"34","author":"Koyuncu","year":"2019","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4681","DOI":"10.1016\/j.bmcl.2012.05.083","article-title":"Ureido-substituted sulfamates show potent carbonic anhydrase IX inhibitory and antiproliferative activities against breast cancer cell lines","volume":"22","author":"Winum","year":"2012","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101297","DOI":"10.1016\/j.redox.2019.101297","article-title":"Carbonic anhydrase 9 confers resistance to ferroptosis\/apoptosis in malignant mesothelioma under hypoxia","volume":"26","author":"Li","year":"2019","journal-title":"Redox. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"92928","DOI":"10.1172\/jci.insight.92928","article-title":"Addition of carbonic anhydrase 9 inhibitor SLC-0111 to temozolomide treatment delays glioblastoma growth in vivo","volume":"2","author":"Boyd","year":"2017","journal-title":"JCI Insight"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/sj.bjc.6605491","article-title":"Circulating tumour cells demonstrate an altered response to hypoxia and an aggressive phenotype","volume":"102","author":"Ameri","year":"2010","journal-title":"Br. J. Cancer"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1158\/0008-5472.CAN-14-3000","article-title":"Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G-CSF production","volume":"75","author":"Chafe","year":"2015","journal-title":"Cancer Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/23\/6080\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:39:31Z","timestamp":1760189971000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/23\/6080"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,2]]},"references-count":49,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["ijms20236080"],"URL":"https:\/\/doi.org\/10.3390\/ijms20236080","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,2]]}}}