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

作者：Marks Isaac S; Gardeen Spencer S; Kurdziel Sarah J; Nicolaou Sonia T; Woods J Evan; Kularatne Sumith A; Low Philip S^*

来源：Molecular Pharmaceutics, 2018, 15(6): 2289-2296.

DOI：10.1021/acs.molpharmaceut.8b00139

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

Carbonic anhydrase IX (CAIX) is a membrane spanning zinc metalloenzyme that catalyzes the reversible consumption of CO2 and water to form H+ + HCO3-. Many human cancers upregulate CAIX to help control the pH in their hypoxic microenvironments. The consequent over expression 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.

• 出版日期2018-6