Targeting carbonic anhydrase IX with small organic ligands

•CAIX plays an important role in tumor acid–base homeostasis under hypoxia.•It is over-expressed in over 90% of renal cell carcinoma.•Inhibition of CAIX can retard tumor growth, inhibit metastasis and deplete tumor stem cells in mice.•Small-molecule ligands of CAIX are promising vehicles for targeted drug delivery applications.

Carbonic anhydrase IX (CAIX) is expressed in many solid tumors in response to hypoxia and plays an important role in tumor acid–base homeostasis under these conditions. It is also constitutively expressed in the majority of renal cell carcinoma. Its functional inhibition with small molecules has recently been shown to retard tumor growth in murine models of cancer, reduce metastasis and tumor stem cell expansion. Additionally, CAIX is a promising antigen for targeted drug delivery approaches. Initially validated with anti-CAIX antibodies, the tumor-homing capacity of high-affinity small-molecule ligands of CAIX has recently been demonstrated. Indeed, conjugates formed of CAIX ligands and potent cytotoxic drugs could eradicate CAIX-expressing solid tumors in mice. These results suggest that CAIX is a promising target for the development of novel therapies for the treatment of solid tumors.