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

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.

Keywords:

• Tail approach
• carbonic anhydrase
• inhibitor
• X-ray crystallography
• hypoxic tumour

Disclosure statement

CT Supuran is Editor-in-Chief of the Journal of Enzyme Inhibition and Medicinal Chemistry. He was not involved in the assessment, peer review, or decision-making process of this article. The authors have no relevant affiliations of financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This project was funded by the Researchers Supporting Project number [RSP-2021/405], King Saud University, Riyadh, Saudi Arabia (SMO) and by the Italian Ministry for University and Research (Ministero dell'Istruzione, dell'Università e della Ricerca [MIUR]), grant PRIN: prot. 2017XYBP2R (CTS).