In several cancers, metastatic tumors often exhibit areas of hypoxia and a decrease in extracellular pH due a shift in their general metabolism. This metabolic shift alters the tumor milieu inducing tumor cell proliferation, angiogenesis, cell motility, invasiveness, and often resistance to common anti-cancer treatments. As a result, tumors exhibiting this phenotype are directly associated with a poorer prognosis and decreased survival rate in cancer patients. Carbonic anhydrase IX (CA IX), an extracellular zinc metalloenzyme, is overexpressed in hypoxic tumors and has been shown to play key roles in tumor physiology. As such, inhibition of CA IX has shown to be therapeutically advantageous in terms of reducing tumor proliferation and increasing tumor susceptibility to radiation and chemotherapies. In addition CA IX has minimal expression in normal human tissues making it an ideal drug target. However targeting CA IX has been challenging since it shares a close homology to other ubiquitously expressed human isoforms, thus presenting the potential for off-target effects. Here we present a novel class of CA IX selective inhibitors that utilize a carbohydrate or acetylated-carbohydrate fragment conjugated to a sulfamate zinc-binding group, and describe the structure-activity relationships that allow these compounds to preferentially bind to CA IX over the ubiquitously expressed CA II. All compounds selectively inhibited CA IX in the nanomolar range (&gt;1000-fold better than other CAs), and also exhibit permeability profiles that favor targeting of extracellular CA IX over the cytosolic CAs. The X-ray crystal structures of five of these compounds in complex with an engineered CA IX-mimic and CA II have been determined to 1.7 Å resolution or better, and demonstrate a selective mechanism of binding between CA IX versus CA II. These inhibitors present promising candidates for anti-CA IX drugs and the treatment for several aggressive cancer types.<br/>

Isoform selective inhibition of tumor-associated carbonic anhydrase IX using carbohydrate-based sulfamates for the treatment of several cancers

249th National Meeting (2015)

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