3BET
Crystal structure of the human carbonic anhydrase II in complex with STX 641 at 1.85 angstroms resolution
Summary for 3BET
| Entry DOI | 10.2210/pdb3bet/pdb |
| Related | 1CA2 2gd8 |
| Descriptor | Carbonic anhydrase 2, ZINC ION, (17beta)-17-(cyanomethyl)-2-methoxyestra-1(10),2,4-trien-3-yl sulfamate, ... (5 entities in total) |
| Functional Keywords | protein-inhibitor complex, disease mutation, lyase, metal-binding |
| Biological source | Homo sapiens (Human) |
| Cellular location | Cytoplasm: P00918 |
| Total number of polymer chains | 1 |
| Total formula weight | 29719.89 |
| Authors | Di Fiore, A.,De Simone, G. (deposition date: 2007-11-20, release date: 2008-10-07, Last modification date: 2023-11-01) |
| Primary citation | Leese, M.P.,Jourdan, F.L.,Gaukroger, K.,Mahon, M.F.,Newman, S.P.,Foster, P.A.,Stengel, C.,Regis-Lydi, S.,Ferrandis, E.,Di Fiore, A.,De Simone, G.,Supuran, C.T.,Purohit, A.,Reed, M.J.,Potter, B.V. Structure-activity relationships of C-17 cyano-substituted estratrienes as anticancer agents J.Med.Chem., 51:1295-1308, 2008 Cited by PubMed Abstract: The synthesis, SAR, and preclinical evaluation of 17-cyanated 2-substituted estra-1,3,5(10)-trienes as anticancer agents are discussed. 2-Methoxy-17beta-cyanomethylestra-1,3,5(10)-trien-3-ol ( 14), but not the related 2-ethyl derivative 7, and the related 3- O-sulfamates 8 and 15 display potent antiproliferative effects (MCF-7 GI 50 300, 60 and 70 nM, respectively) against human cancer cells in vitro. Investigation of the SAR reveals that a sterically unhindered hydrogen bond acceptor attached to C-17 is most likely key to the enhanced activity. Compound 8 displayed significant in vitro antiangiogenic activity, and its ability to act as a microtubule disruptor was confirmed. Inhibitory activity of the sulfamate derivatives against steroid sulfatase and carbonic anhydrase II (hCAII) was also observed, and the interaction between 15 and hCAII was investigated by protein crystallography. The potential of these multimechanism anticancer agents was confirmed in vivo, with promising activity observed for both 14 and 15 in an athymic nude mouse MDA-MB-231 human breast cancer xenograft model. PubMed: 18260615DOI: 10.1021/jm701319c PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.85 Å) |
Structure validation
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