The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII
| Autor: | Alessandro Bonardi, Silvia Bua, Jacob Combs, Carrie Lomelino, Jacob Andring, Sameh Mohamed Osman, Alessandra Toti, Lorenzo Di Cesare Mannelli, Paola Gratteri, Carla Ghelardini, Robert McKenna, Alessio Nocentini, Claudiu T. Supuran |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 37, Iss 1, Pp 930-939 (2022) |
| Druh dokumentu: | article |
| ISSN: | 14756366 1475-6374 1475-6366 |
| DOI: | 10.1080/14756366.2022.2053526 |
| Popis: | Human (h) carbonic anhydrase (CAs, EC 4.2.1.1) isoforms IX and XII were recently confirmed as anticancer targets against solid hypoxic tumours. The “three-tails approach” has been proposed as an extension of the forerunner “tail” and “dual-tail approach” to fully exploit the amino acid differences at the medium/outer active site rims among different hCAs and to obtain more isoform-selective inhibitors. Many three-tailed inhibitors (TTIs) showed higher selectivity against the tumour-associated isoforms hCA IX and XII with respect to the off-targets hCA I and II. X-ray crystallography studies were performed to investigate the binding mode of four TTIs in complex with a hCA IX mimic. The ability of the most potent and selective TTIs to reduce in vitro the viability of colon cancer (HT29), prostate adenocarcinoma (PC3), and breast cancer (ZR75-1) cell lines was evaluated in normoxic (21% O2) and hypoxic (3% O2) conditions demonstrating relevant anti-proliferative effects. |
| Databáze: | Directory of Open Access Journals |
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