<p>Experimental Carbonic Anhydrase Inhibitors for the Treatment of Hypoxic Tumors</p>

Abstract

Carbonic anhydrase (CA, EC 4.2.1.1) isoforms IX and XII are overexpressed in many hypoxic tumors as a consequence of the hypoxia inducible factor (HIF) activation cascade, being present in limited amounts in normal tissues. These enzymes together with many others are involved in the pH regulation and metabolism of hypoxic cancer cells, and were validated as antitumor targets recently. A multitude of targeting strategies against these enzymes have been proposed and are reviewed in this article. The small molecule inhibitors, small molecule drug conjugates (SMDCs), antibody-drug conjugates (ADACs) or cytokine-drug conjugates but not the monoclonal antibodies against CA IX/XII will be discussed. Relevant synthetic chemistry efforts, coupled with a multitude of preclinical studies, demonstrated that CA IX/XII inhibition leads to the inhibition of growth of primary tumors and metastases and depletes cancer stem cell populations, all factors highly relevant in clinical settings. One small molecule inhibitor, sulfonamide SLC-0111, is the most advanced candidate, having completed Phase I and being now in Phase Ib/II clinical trials for the treatment of advanced hypoxic solid tumors.

Reconsidering anion inhibitors in the general context of drug design studies of modulators of activity of the classical enzyme carbonic anhydrase

“…All these studies confirmed the usefulness of this clinical candidate, SLC-0111, in tumours and other biomedical conditions. Although Jonsson and Liljas presumably read our reply 180 , in their reply to our reply they continue that they, “would have liked to see a properly reported inhibition study of this compound to make it obvious that it indeed is a good enough inhibitor to enter Phase I/Phase II studies” 181 .…”

“…We have replied to the technical issues raised by Jonsson and Liljas, as mentioned above. In their comment on our reply 180 they indicated they were “ happy by our prompt response ” and that some clarifications were achieved 181 , however now their criticism relating to the measurement of inhibition constants was extended to the entire medicinal chemistry community, not only to our group, stating that the “ original article was not intended to raise specific concerns regarding just one research group but rather was intended to raise concerns regarding medicinal chemistry publications in general, and we are glad that Prof. Supuran agrees that there is room for improvement! ” CTS hardly agrees with anything from their analysis.…”

“…This action was based on some typographical errors found in Supplementary Information from 5 papers from our group (among the > 1600 that have been published). We have replied to the above-mentioned article 178 in an Editorial published in the same journal 179 as well as two additional review articles 153 , 180 . Jonsson and Liljas replied to our editorial 179 with a new comment published recently 181 .…”

Inhibition of Carbonic Anhydrase IX Promotes Apoptosis through Intracellular pH Level Alterations in Cervical Cancer Cells

“…On the other hand, many studies indicated that inhibiting this enzyme has a therapeutic effect on primary tumour and metastases growth [ 18 , 19 ]. These findings were relevant for the validation of CAIX as an anticancer therapeutic target [ 20 , 21 ].…”

“…Sulphonamide derivatives acting as effective CAIX inhibitors showed significant anticancer activity in vitro and/or in vivo in many cell types and cancer models, with one such compound, SLC-0111, presently in Phase Ib/II clinical trials for the management of advanced, metastatic solid tumours [ 18 , 21 ]. Small-molecule CAIX inhibitors [ 21 ], but also small-molecule drug conjugates, antibody-drug conjugates, or cytokine-drug conjugates, targeting these enzymes were demonstrated to constitute an innovative antitumor strategy in the last decade [ 22 ]. In the present study, the cytotoxic effects of a sulphonamide CAIX inhibitor, derivative compound E (4-(2-((5-bromo-2-hydroxybenzyl) amino) ethyl) benzenesulphonamide), were investigated in the cancer cells with high CAIX expression.…”