Development of a Small Molecule Tubulysin B Conjugate for Treatment of Carbonic Anhydrase IX Receptor Expressing Cancers

Isaac S. Marks, Spencer S. Gardeen, Sarah J. Kurdziel, Sonia T. Nicolaou, J. Evan Woods, Sumith A. Kularatne, Philip S. Low

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


Carbonic anhydrase IX (CAIX) is a membrane-spanning zinc metalloenzyme that catalyzes the reversible consumption of CO 2 and water to form H + + HCO 3 - . Many human cancers upregulate CAIX to help control the pH in their hypoxic microenvironments. The consequent overexpression of CAIX on malignant cells and low expression on normal tissues render CAIX a particularly attractive target for small molecule inhibitors, antibody-drug conjugates, and ligand-targeted drugs. In this study, CAIX-targeted fluorescent reporter molecules were initially exploited to investigate CAIX-specific binding to multiple cancer cell lines, where they were shown to display potent and selective binding to CAIX positive cells. A small molecule CAIX-targeted tubulysin B conjugate was then synthesized and examined for its ability to kill CAIX-expressing tumor cells in vitro. Potent therapeutic conjugates were subsequently tested in vivo and demonstrated to eliminate solid human tumor xenografts in murine tumor models without exhibiting overt signs of toxicity. Because most solid tumors contain hypoxic regions where CAIX is overexpressed, development of a method to selectively deliver drugs to these hypoxic regions could aid in the therapy of otherwise difficult to treat tumors.

Original languageEnglish (US)
Pages (from-to)2289-2296
Number of pages8
JournalMolecular pharmaceutics
Issue number6
StatePublished - Jun 4 2018


  • carbonic anhydrase IX
  • drug targeting
  • ligand-targeted therapy
  • small molecule drug conjugate
  • tubulysin chemotherapy
  • tumor-specific receptor

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmaceutical Science
  • Drug Discovery


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