Design, Synthesis, and Biological Evaluation of Hydroquinone Derivatives of 17-Amino-17-demethoxygeldanamycin as Potent, Water-Soluble Inhibitors of Hsp90
- 29 June 2006
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 49 (15), 4606-4615
- https://doi.org/10.1021/jm0603116
Abstract
17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.Keywords
This publication has 35 references indexed in Scilit:
- Phase I Pharmacokinetic and Pharmacodynamic Study of 17-Allylamino, 17-Demethoxygeldanamycin in Patients With Advanced MalignanciesJournal of Clinical Oncology, 2005
- Independent ATPase Activity of Hsp90 Subunits Creates a Flexible Assembly PlatformJournal of Molecular Biology, 2004
- IC101 Induces Apoptosis by Akt Dephosphorylation via an Inhibition of Heat Shock Protein 90-ATP Binding Activity Accompanied by Preventing the Interaction with Akt in L1210 CellsThe Journal of pharmacology and experimental therapeutics, 2004
- Induction of Hsp90 protein expression in malignant melanomas and melanoma metastasesExperimental Dermatology, 2004
- Structure of the N-terminal Domain of GRP94: BASIS FOR LIGAND SPECIFICITY AND REGULATIONOnline Journal of Public Health Informatics, 2003
- The rules of attractionNature, 2003
- Ligand Interactions in the Adenosine Nucleotide-binding Domain of the Hsp90 Chaperone, GRP94Online Journal of Public Health Informatics, 2000
- Geldanamycin-Induced Destabilization of Raf-1 Involves the ProteasomeBiochemical and Biophysical Research Communications, 1997
- Analysis of heat-shock protein expression in myeloid leukaemia cells by flow cytometryBritish Journal of Haematology, 1995
- Clinical and biological significance of HSP89 alpha in human breast cancerInternational Journal of Cancer, 1992