Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Abstract

The tumor microenvironment is crucial for the growth of cancer cells, triggering particular biochemical and physiological changes, which frequently influence the outcome of anticancer therapies. The biochemical rationale behind many of these phenomena resides in the activation of transcription factors such as hypoxia-inducible factor 1 and 2 (HIF-1/2). In turn, the HIF pathway activates a number of genes including those involved in glucose metabolism, angiogenesis, and pH regulation. Several carbonic anhydrase (CA, EC 4.2.1.1) isoforms, such as CA IX and XII, actively participate in these processes and were validated as antitumor/antimetastatic drug targets. Here, we review the field of CA inhibitors (CAIs), which selectively inhibit the cancer-associated CA isoforms. Particular focus was on the identification of lead compounds and various inhibitor classes, and the measurement of CA inhibitory on-/off-target effects. In addition, the preclinical data that resulted in the identification of SLC-0111, a sulfonamide in Phase Ib/II clinical trials for the treatment of hypoxic, advanced solid tumors, are detailed.

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

“…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 .…”

PEG Linker Length Strongly Affects Tumor Cell Killing by PEGylated Carbonic Anhydrase Inhibitors in Hypoxic Carcinomas Expressing Carbonic Anhydrase IX

“…Based on the crystal structure of the dimeric CA IX [ 51 ], one can calculate that even the PEG 1K is long enough to allow positioning of the two warheads of the PEGylated bis-sulfonamide in the two individual active sites of the CA IX dimer. This cooperative mechanism of action may be different from the interaction of CA IX with classical monodentate inhibitors [ 8 , 26 , 79 , 80 ] and warrants further investigations.…”

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

“…They state that “it is doubtful that SLC-0111 has the required Ki to advance to clinical trials” and that the “commercial interests of pharmaceutical companies and patients may be hurt”. 145 As shown in this review, and elsewhere, as a reply to this attack, 53 , 146 a multitude of studies form various laboratories all over the world, through an effort of more than 20 years, allowed the validation of the two enzymes as drug targets. Furthermore, very diverse techniques such as stopped-flow kinetics, 53 native mass spectrometry measurements, 147–149 and X-ray crystallography strongly support the Ki values obtained in our laboratory using the stopped-flow kinetic method for a range of different types of CAIs and demonstrate that this provides sufficient accuracy levels for drug discovery and development applications.…”

“… 145 As shown in this review, and elsewhere, as a reply to this attack, 53 , 146 a multitude of studies form various laboratories all over the world, through an effort of more than 20 years, allowed the validation of the two enzymes as drug targets. Furthermore, very diverse techniques such as stopped-flow kinetics, 53 native mass spectrometry measurements, 147–149 and X-ray crystallography strongly support the Ki values obtained in our laboratory using the stopped-flow kinetic method for a range of different types of CAIs and demonstrate that this provides sufficient accuracy levels for drug discovery and development applications. It should also be noted that more than 10,000 different CAIs were synthesized and assayed in our laboratory and a number of >15,000 were assayed through collaborations with >100 academic research groups and 15 pharmaceutical companies worldwide during the three decades of activity in CA research.…”