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

• Main Authors: Alessandro Bonardi (Author), Silvia Bua (Author), Jacob Combs (Author), Carrie Lomelino (Author), Jacob Andring (Author), Sameh Mohamed Osman (Author), Alessandra Toti (Author), Lorenzo Di Cesare Mannelli (Author), Paola Gratteri (Author), Carla Ghelardini (Author), Robert McKenna (Author), Alessio Nocentini (Author), Claudiu T. Supuran (Author)
• Format: Book
• Published: Taylor & Francis Group, 2022-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

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.

Item Description

10.1080/14756366.2022.2053526
1475-6374
1475-6366