3R92
Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.
Summary for 3R92
| Entry DOI | 10.2210/pdb3r92/pdb |
| Descriptor | Heat shock protein HSP 90-alpha, (3aR)-13,13,16-trimethyl-15-oxo-1,2,3,3a,4,5,12,14,15,17,18,19-dodecahydro-13H-10,6-(metheno)pyrrolo[2',1':3,4][1,4,9]triazacyclotetradecino[9,8-a]indole-7-carboxamide (3 entities in total) |
| Functional Keywords | chaperone, atp binding domain, atp-binding, nucleotide-binding, phosphoprotein, stress response, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 25847.14 |
| Authors | Zapf, C.W.,Bloom, J.D.,McBean, J.L.,Dushin, R.G.,Golas, J.M.,Liu, H.,Lucas, J.,Boschelli, F.,Vogan, E.M.,Levin, J.I. (deposition date: 2011-03-24, release date: 2011-06-08, Last modification date: 2024-02-21) |
| Primary citation | Zapf, C.W.,Bloom, J.D.,McBean, J.L.,Dushin, R.G.,Golas, J.M.,Liu, H.,Lucas, J.,Boschelli, F.,Vogan, E.,Levin, J.I. Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model. Bioorg.Med.Chem.Lett., 21:3627-3631, 2011 Cited by PubMed Abstract: A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth. PubMed: 21605975DOI: 10.1016/j.bmcl.2011.04.102 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5801 Å) |
Structure validation
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