4O04
Identification of novel HSP90/isoform selective inhibitors using structure-based drug design. Demonstration of potential utility in treating CNS disorders such as Huntington's disease
Summary for 4O04
| Entry DOI | 10.2210/pdb4o04/pdb |
| Related | 4O05 4O06 4O09 4O0B |
| Descriptor | Heat shock protein HSP 90-alpha, 4-(2,7,7-trimethyl-5-oxo-1,2,3,4,5,6,7,8-octahydro-9H-beta-carbolin-9-yl)benzamide (3 entities in total) |
| Functional Keywords | chaperone, chaperone-chaperone inhibitor complex, chaperone/chaperone inhibitor |
| Biological source | Homo sapiens (human) |
| Cellular location | Cytoplasm : P07900 |
| Total number of polymer chains | 1 |
| Total formula weight | 26534.84 |
| Authors | Zuccola, H.J.,Ernst, J. (deposition date: 2013-12-13, release date: 2014-12-24, Last modification date: 2024-02-28) |
| Primary citation | Ernst, J.T.,Neubert, T.,Liu, M.,Sperry, S.,Zuccola, H.,Turnbull, A.,Fleck, B.,Kargo, W.,Woody, L.,Chiang, P.,Tran, D.,Chen, W.,Snyder, P.,Alcacio, T.,Nezami, A.,Reynolds, J.,Alvi, K.,Goulet, L.,Stamos, D. Identification of Novel HSP90 alpha / beta Isoform Selective Inhibitors Using Structure-Based Drug Design. Demonstration of Potential Utility in Treating CNS Disorders such as Huntington's Disease. J.Med.Chem., 57:3382-3400, 2014 Cited by PubMed Abstract: A structure-based drug design strategy was used to optimize a novel benzolactam series of HSP90α/β inhibitors to achieve >1000-fold selectivity versus the HSP90 endoplasmic reticulum and mitochondrial isoforms (GRP94 and TRAP1, respectively). Selective HSP90α/β inhibitors were found to be equipotent to pan-HSP90 inhibitors in promoting the clearance of mutant huntingtin protein (mHtt) in vitro, however with less cellular toxicity. Improved tolerability profiles may enable the use of HSP90α/β selective inhibitors in treating chronic neurodegenerative indications such as Huntington's disease (HD). A potent, selective, orally available HSP90α/β inhibitor was identified (compound 31) that crosses the blood-brain barrier. Compound 31 demonstrated proof of concept by successfully reducing brain Htt levels following oral dosing in rats. PubMed: 24673104DOI: 10.1021/jm500042s PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.82 Å) |
Structure validation
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