Screening Campaign and Docking Investigations in Identifying New Hit Compounds as Inhibitors of Human Carbonic Anhydrases Expressed In Tumour Cells

The tumor-expressed human carbonic anhydrase (hCA) isoforms hCA IX and hCA XII have been extensively studied to develop anticancer agents targeting solid tumors in combined therapy. These CA isoforms are considered key factors in controlling tumor microenvironment (TME) of cancer lines that develop high metastatic activity. Herein, we report the discovery of potent hCA IX/hCA XII inhibitors that were disclosed through a screening campaign on an in-house collection of arylsulfonamides preliminary tested toward other hCAs. Among them, the N-(4-sulfamoylphenyl)naphthalene-2-carboxamide (12) and N-(4-sulfamoylphenyl)-3,4-dihydroisoquinoline-2(1H)-carbothioamide (15) proved to be the most intriguing hCA IX/hCA XII inhibitors displaying favourable selectivity ratios over widespread hCA I and hCA II isoforms. To explore their binding mode, we conducted docking studies that described the poses of the best inhibitors in the catalytic site of hCA IX and hCA XII, thus suggesting the privileged pattern of interactions. These structural findings might further improve the knowledge for a successful identification of new sulfonamides as adjuvant agents in cancer management. We explored our in-house collection of sulfonamides to identify new potent hCA IX/XII inhibitors. Docking simulations highlighted the docking poses in catalytic sites of hCA IX and hCA XII cavities. These structural findings may help lead to the successful identification of new sulfonamides as adjuvant agents in cancer management.image

Automated summary

This study reports the discovery of potent inhibitors targeting hCA IX and hCA XII, two isoforms that play a key role in controlling the tumor microenvironment. Through screening arylsulfonamides compounds, two most promising inhibitors were identified with favorable selectivity ratios against other isoforms. Docking studies provided insights into the binding mode of these inhibitors, which can contribute to the development of new sulfonamides as adjuvant agents in cancer management.