: 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.

The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII / Bonardi, Alessandro; Bua, Silvia; Combs, Jacob; Lomelino, Carrie; Andring, Jacob; Osman, Sameh Mohamed; Toti, Alessandra; Di Cesare Mannelli, Lorenzo; Gratteri, Paola; Ghelardini, Carla; McKenna, Robert; Nocentini, Alessio; Supuran, Claudiu T. - In: JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY. - ISSN 1475-6366. - ELETTRONICO. - 37:(2022), pp. 930-939-939. [10.1080/14756366.2022.2053526]

The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII

Bonardi, Alessandro;Bua, Silvia;Toti, Alessandra;Di Cesare Mannelli, Lorenzo;Gratteri, Paola;Ghelardini, Carla;Nocentini, Alessio
;
Supuran, Claudiu T
2022

Abstract

: 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.
2022
37
930-939
939
Bonardi, Alessandro; Bua, Silvia; Combs, Jacob; Lomelino, Carrie; Andring, Jacob; Osman, Sameh Mohamed; Toti, Alessandra; Di Cesare Mannelli, Lorenzo; Gratteri, Paola; Ghelardini, Carla; McKenna, Robert; Nocentini, Alessio; Supuran, Claudiu T
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Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1262779
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