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.
J Enzyme Inhib Med Chem. 2022 Dec;37(1):930-939. doi: 10.1080/14756366.2022.2053526.
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 the viability of colon cancer (HT29), prostate adenocarcinoma (PC3), and breast cancer (ZR75-1) cell lines was evaluated in normoxic (21% O) and hypoxic (3% O) conditions demonstrating relevant anti-proliferative effects.
人（h）碳酸酐酶（CAs，EC 4.2.1.1）同工型 IX 和 XII 最近被确认为针对实体缺氧肿瘤的抗癌靶标。“三尾策略”被提议作为先驱“尾巴”和“双尾策略”的扩展，以充分利用不同 hCAs 中中/外活性位点边缘的氨基酸差异，并获得更多的同工型选择性抑制剂。许多三尾抑制剂（TTIs）在针对肿瘤相关同工型 hCA IX 和 XII 方面表现出更高的选择性，相对于脱靶 hCA I 和 II。进行了 X 射线晶体学研究，以研究与 hCA IX 模拟物复合的四种 TTIs 的结合模式。在常氧（21% O）和缺氧（3% O）条件下，评估了最有效和选择性最强的 TTIs 降低结肠癌细胞（HT29）、前列腺腺癌（PC3）和乳腺癌（ZR75-1）细胞系活力的能力，证明了相关的抗增殖作用。
