review · Metabolites
The tumour microenvironment plays an essential role in cancer progression, driving biochemical and physiological alterations that often impact the effectiveness of anticancer treatments. Many of these alterations stem from the activation of hypoxia-inducible factors, which govern genes involved in glucose metabolism, blood vessel formation, and pH control. Within these pathways, specific carbonic anhydrase enzymes, notably isoforms IX and XII, have been confirmed as viable targets for antitumor and antimetastatic therapies. Research focuses on developing selective carbonic anhydrase inhibitors to target these specific cancer-linked isoforms while assessing on-target and off-target effects across different chemical classes. Preclinical investigations have supported the emergence of promising lead compounds, including the sulfonamide candidate SLC-0111. This compound has advanced into early-phase clinical trials specifically addressing hypoxic, advanced solid tumours, demonstrating the therapeutic potential of targeting pH regulation and metabolic adaptations in malignant cells.
Cancer cells often adapt to low-oxygen environments by altering their metabolism and internal acidity, which makes them harder to treat with standard therapies. By understanding how to selectively block enzymes responsible for maintaining this protective environment, researchers can design more targeted therapies that disrupt cancer cell survival and spread, potentially offering new options for patients with advanced or treatment-resistant tumours.
The development of selective carbonic anhydrase inhibitors targets pharmaceutical developers creating treatments for hypoxic, advanced solid tumours. While much of the inhibitor discovery and class characterisation remains at the lead identification and preclinical stage, translational progress is evident. For instance, the candidate SLC-0111 has advanced into Phase Ib/II clinical trials, indicating that certain applications of this therapeutic approach are in active clinical development rather than purely early laboratory research.
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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.
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DOI: 10.3390/metabo10100412
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