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.

中文翻译：

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碳酸酐酶抑制剂靶向代谢和肿瘤微环境。

肿瘤微环境对于癌细胞的生长至关重要，它会触发特定的生化和生理变化，从而经常影响抗癌治疗的结果。这些现象背后的生化原理在于转录因子的激活，例如缺氧诱导因子1和2（HIF-1 / 2）。反过来，HIF途径激活了许多基因，包括与葡萄糖代谢，血管生成和pH调节有关的基因。几种碳酸酐酶（CA，EC 4.2.1.1）同工型，如CA IX和XII，积极参与了这些过程，并被确认为抗肿瘤/抗转移药物的靶标。在这里，我们回顾了CA抑制剂（CAIs）的领域，其选择性抑制癌症相关的CA同工型。特别关注的是铅化合物和各种抑制剂种类的鉴定，以及CA抑制靶标/靶标效应的测量。此外，还详细介绍了在Sb-0111期Ib / II期临床试验中鉴定出磺胺类药物SLC-0111的临床前数据，该药物用于治疗低氧，晚期实体瘤。