Inhibition of Carbonic Anhydrase Using SLC-149: Support for a Noncatalytic Function of CAIX in Breast Cancer.
J Med Chem
; 64(3): 1713-1724, 2021 02 11.
Article
en En
| MEDLINE
| ID: mdl-33523653
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
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Inhibidores de Anhidrasa Carbónica
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Anhidrasa Carbónica IX
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Antineoplásicos
Límite:
Female
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2021
Tipo del documento:
Article
País de afiliación:
Estados Unidos