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.

Details

Title
The three-tails approach as a new strategy to improve selectivity of action of sulphonamide inhibitors against tumour-associated carbonic anhydrase IX and XII
Author
Bonardi, Alessandro 1 ; Bua, Silvia 2 ; Combs, Jacob 3 ; Lomelino, Carrie 3 ; Andring, Jacob 3 ; Sameh Mohamed Osman 4 ; Toti, Alessandra 2   VIAFID ORCID Logo  ; Lorenzo Di Cesare Mannelli 2   VIAFID ORCID Logo  ; Gratteri, Paola 5 ; Ghelardini, Carla 2 ; McKenna, Robert 3 ; Nocentini, Alessio 2   VIAFID ORCID Logo  ; Supuran, Claudiu T 2   VIAFID ORCID Logo 

1  Department NEUROFARBA – Pharmaceutical and Nutraceutical Section, University of Firenze, Florence, Italy; Department NEUROFARBA – Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Florence, Italy 
2  Department NEUROFARBA – Pharmaceutical and Nutraceutical Section, University of Firenze, Florence, Italy 
3  Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL, USA 
4  Chemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia 
5  Department NEUROFARBA – Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Florence, Italy 
Pages
930-939
Publication year
2022
Publication date
Dec 2022
Publisher
Taylor & Francis Ltd.
ISSN
14756366
e-ISSN
14756374
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1080/14756366.2022.2053526
ProQuest document ID
2727916084
Copyright
© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This work is licensed under the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.