Targeting carbonic anhydrase IX with small organic ligands

Moreno Wichert; Nikolaus Krall

doi:10.1016/j.cbpa.2015.02.005

Targeting carbonic anhydrase IX with small organic ligands

Curr Opin Chem Biol. 2015 Jun:26:48-54. doi: 10.1016/j.cbpa.2015.02.005. Epub 2015 Feb 24.

Authors

Moreno Wichert¹, Nikolaus Krall²

Affiliations

¹ ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland.
² ETH Zurich, Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, 8093 Zurich, Switzerland. Electronic address: nikolaus.krall@pharma.ethz.ch.

PMID: 25721398
DOI: 10.1016/j.cbpa.2015.02.005

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Acetazolamide / analogs & derivatives
Acetazolamide / chemical synthesis
Acetazolamide / metabolism
Acetazolamide / pharmacology*
Animals
Antigens, Neoplasm / chemistry*
Antigens, Neoplasm / metabolism
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology*
Carbonic Anhydrase IX
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / metabolism
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / chemistry*
Carbonic Anhydrases / metabolism
Cell Line, Tumor
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / enzymology
Colorectal Neoplasms / pathology
Humans
Ligands
Mice
Molecular Targeted Therapy
Protein Multimerization
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / metabolism
Small Molecule Libraries / pharmacology*
Xenograft Model Antitumor Assays

Substances

Antigens, Neoplasm
Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Ligands
Small Molecule Libraries
CA9 protein, human
Carbonic Anhydrase IX
Carbonic Anhydrases
Acetazolamide