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Review
. 2020 Oct 14;10(10):412.
doi: 10.3390/metabo10100412.

Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Andrea Angeli  1 , Fabrizio Carta  1 , Alessio Nocentini  1 , Jean-Yves Winum  2 , Raivis Zalubovskis  3 , Atilla Akdemir  4 , Valentina Onnis  5 , Wagdy M Eldehna  6 , Clemente Capasso  7 , Giuseppina De Simone  8 , Simona Maria Monti  8 , Simone Carradori  9 , William A Donald  10 , Shoukat Dedhar  11 , Claudiu T Supuran  1
Affiliations
Review

Carbonic Anhydrase Inhibitors Targeting Metabolism and Tumor Microenvironment

Andrea Angeli et al. Metabolites. .

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.

Keywords: SLC-0111; carbonic anhydrase; hypoxia; inhibitor; pH regulation; sulfonamide.

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Conflict of interest statement

All authors except F.C., S.D. and C.T.S. declare no conflict of interest. F.C., S.D. and C.T.S. are inventors of SLC-0111. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

Figures

Figure 1
Figure 1
Carbonic anhydrase inhibitors (CAIs) that were crucial for validation of CA IX/XII as antitumor targets: acetazolamide 1 is the classical inhibitor in clinical use for decades; the fluorescein-derivatized sulfonamides 2 and 3 were used in the proof of concept studies to demonstrate the involvement of CA IX in acidification of the external pH of the tumor cell [47,48,49,50], the ureido-substituted-sulfonamides 4 and 5 were among the first CAIs to show significant antitumor effects in animal models of hypoxic tumors [51,52], together with coumarin inhibitors 6 and 7 [53].
Figure 2
Figure 2
Chemical structures for SLC-0111 analogs (8–10) developed through modification of the SLC-0111 benzenesulfonamide moiety.
Figure 3
Figure 3
Chemical structures for SLC-0111 analogs (11–16) developed through modification of the SLC-0111 ureido linker.
Figure 4
Figure 4
Chemical structures for SLC-0111 analogs (17–23) developed through modification of the SLC-0111 tail.
Figure 5
Figure 5
Design of the N-(un)substituted isatins-SLC-0111 hybrids 24 and 25 [157,158].
See this image and copyright information in PMC

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