Inhibition of Carbonic Anhydrase Using SLC-149: Support for a Noncatalytic Function of CAIX in Breast Cancer

Carbonic anhydrase
IX (CAIX) is considered a target for therapeutic
intervention in solid tumors. In this study, the efficacy of the inhibitor,
4-(3-(2,4-difluorophenyl)-oxoimidazolidin-1-yl)­benzenesulfonamide
(SLC-149), is evaluated on CAIX and a CAIX-mimic. We show that SLC-149
is a better inhibitor than acetazolamide against CAIX. Binding of
SLC-149 thermally stabilizes CAIX-mimic at lower concentrations compared
to that of CAII. Structural examinations of SLC-149 bound to CAIX-mimic
and CAII explain binding preferences. In cell culture, SLC-149 is
a more effective inhibitor of CAIX activity in a triple-negative breast
cancer cell line than previously studied sulfonamide inhibitors. SLC-149
is also a better inhibitor of activity in cells expressing CAIX versus
CAXII. However, SLC-149 has little effect on cytotoxicity, and high
concentrations are required to inhibit cell growth, migration, and
invasion. These data support the hypothesis that CAIX activity, shown
to be important in regulating extracellular pH, does not underlie
its ability to control cell growth.