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Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers

1
Faculty of Biology, Medicine and Health, School of Pharmacy and Optometry, University of Manchester, Manchester M13 9PL, UK
2
Faculty of Health and Life Sciences, Department of Applied Sciences, University of Northumbria, Newcastle Upon Tyne NE1 8ST, UK
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(23), 6080; https://doi.org/10.3390/ijms20236080
Received: 5 November 2019 / Revised: 28 November 2019 / Accepted: 29 November 2019 / Published: 2 December 2019
(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors, II)
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. View Full-Text
Keywords: carbonic anhydrases (CAs); ureido-substituted benzenesulfonamide; ureido-substituted sulfamate; CAIX/XII inhibitors; hypoxia; S4; U-104; SLC-0111 carbonic anhydrases (CAs); ureido-substituted benzenesulfonamide; ureido-substituted sulfamate; CAIX/XII inhibitors; hypoxia; S4; U-104; SLC-0111
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Williams, K.J.; Gieling, R.G. Preclinical Evaluation of Ureidosulfamate Carbonic Anhydrase IX/XII Inhibitors in the Treatment of Cancers. Int. J. Mol. Sci. 2019, 20, 6080.

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