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.
Highlights
The microenvironment of tumor cells is different from that of normal cells and plays a crucial role in shaping the behavior of tumors, which, in turn, frequently influences treatment outcomes as well as treatment strategies [1,2]
I values for inhibitors that bind at the site of the substrate, which is the case for sulfonamide CA inhibitors (CAIs)
Compound 5 is characterized by the presence of the ureido functionality as a linker between the benzenesulfonamide fragment and the tail of the inhibitor
Summary
The microenvironment of tumor cells is different from that of normal cells and plays a crucial role in shaping the behavior of tumors, which, in turn, frequently influences treatment outcomes as well as treatment strategies [1,2]. The 2-hydroxycinnamic acids formed by coumarin hydrolysis do not interact with the catalytic metal ion but instead bind at the entrance of the active site cavity, in a highly variable region of the different CA isoforms, which explains the very isoform-selective inhibitory effects of many representatives of this class of CAIs [82,83,84,85] This new CA inhibitory class inspired the discovery of many other chemotypes, such as the sulfocoumarins and the homosulfocoumarins by Zalubovskis group [86,87,88], the homocoumarins [89], the thiocoumarins by Ferraroni et al [90], etc. One of the strangest CA inhibition mechanism is the one reported by De Simone’s and Carradori’s group for a benzoic acid derivative that binds outside the active site cavity [111]
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