Oral Presentation RACI Biomolecular Division Conference 2013

Medicinal chemistry of carbonic anhydrase inhibitors targeting tumour hypoxia (#10)

Sally-Ann Poulsen 1
  1. Eskitis Institute for Drug Discovery, Griffith University, Nathan, Queensland, Australia

This presentation will describe recent aspects of our medicinal chemistry research program in which we focus on the development of therapeutic and diagnostic agents for oncology, specificall tumour hypoxia.

Carbonic anhydrases (CAs) are zinc metalloenzymes that catalyse the reversible hydration of carbon dioxide to bicarbonate and a proton.1  CA isozymes IX and XII are overexpressed in many hypoxic tumors where they provide a pH-regulating system that contributes to hypoxic tumor cell survival and proliferation.23  The significance of CAs role in cancer has triggered a need to develop novel, drug-like small molecules that selectively target cancer-associated CAs for use as chemical tools and/or as leads for therapeutic drug discovery. Selective inhibition among CA isozymes is a challenging hurdle and for the CA enzyme family conservation of active site structure and topology has made it difficult to target subtle isozyme differences by rational drug design. We are exploring an alternate strategy towards isozyme selectivity that takes in to account the relevant biological landscape for both normal and cancerous cells or tissues associated with CAs. This presentation will describe recent aspects of our medicinal chemistry research program that focuses on the development of future therapeutic molecules that target CA. Our research builds on the ‘tail’ approach for the development of CA inhibitors - wherein the zinc binding sulfonamide group (-SO2NH2), is functionalised with variable ‘tail’ fragments. This design strategy provides an avenue to investigate structure-activity relationships (SAR) as well as to impart desirable physicochemical properties (i.e. structure-property relationships – SPR) into the CA inhibitor molecules.

  1. Krishnamurthy, V. M.; Kaufman, G. K.; Urbach, A. R.; Gitlin, I.; Gudiksen, K. L.; Weibel, D. B.; Whitesides, G. M., Carbonic Anhydrase as a Model for Biophysical and Physical-Organic Studies of Proteins and Protein-Ligand Binding. Chem. Rev. 2008, 108, 946-1051.
  2. Chiche, J.; Ilc, K.; Laferriere, J.; Trottier, E.; Dayan, F.; Mazure, N. M.; Brahimi-Horn, M. C.; Pouyssegur, J., Hypoxia-Inducible Carbonic Anhydrase IX and XII Promote Tumor Cell Growth by Counteracting Acidosis through the Regulation of the Intracellular pH. Cancer Res. 2009, 69, 358-368.
  3. Neri, D.; Supuran, C. T., Interfering with pH regulation in tumours as a therapeutic strategy. Nat. Rev. Drug Discovery 2011, 10, 767-777.