6NM0
Selective inhibition of carbonic anhydrase IX activity, using compound SLC-149, displays limited anticancer effects in breast cancer cell lines
Summary for 6NM0
| Entry DOI | 10.2210/pdb6nm0/pdb |
| Descriptor | Carbonic anhydrase 2, ZINC ION, 4-[3-(2,4-difluorophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]benzene-1-sulfonamide, ... (6 entities in total) |
| Functional Keywords | breast cancer, hypoxia, lyase, lyase-lyase inhibitor complex, lyase/lyase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 29519.61 |
| Authors | Singh, S.,McKenna, R. (deposition date: 2019-01-10, release date: 2020-01-15, Last modification date: 2023-10-11) |
| Primary citation | Mboge, M.Y.,Combs, J.,Singh, S.,Andring, J.,Wolff, A.,Tu, C.,Zhang, Z.,McKenna, R.,Frost, S.C. Inhibition of Carbonic Anhydrase Using SLC-149: Support for a Noncatalytic Function of CAIX in Breast Cancer. J.Med.Chem., 64:1713-1724, 2021 Cited by PubMed 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. PubMed: 33523653DOI: 10.1021/acs.jmedchem.0c02077 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.44 Å) |
Structure validation
Download full validation report
