Description
Geldanamycin is a potent inhibitor of Hsp90 that has poor water solubility. 17-
DMAG is a water-
soluble derivative of geldanamycin which potently inhibits Hsp90 (IC
50 = 24 nM) and has excellent bioavailability and tissue distribution in animals. Like other Hsp90 inhibitors, 17-
DMAG has diverse anti-
tumor actions and has potential in treating certain types of cancer. This compound also suppresses inflammation by interfering with signaling through the NF-
κB pathway. 17-
DMAG also ameliorates high fat diet-
induced renal failure in a mouse model of diabetes.
Biological Activity
Water-soluble analog of 17-AAG (17-Demethoxy-17-(2-propenylamino)geldanamycin ) and geldanamycin (9,13-Dihydroxy-8,14,19-trimethoxy-4,10,12,16-tetramethyl-2-azabicyclo[16.3.1]docosa-4,6,10,18,21-pentaene-3,20,22-trione, 9-carbamate ). Binds the ATP binding site of Hsp90 and inhibits its chaperone activity. Displays more potent antitumor activity than 17-AAG (mean GI 50 values are 53 and 123 nM for 17-DMAG and 17-AAG respectively).
References
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10.1007/s00280-001-0380-8[2] ELIZABETH E A BULL. Enhanced tumor cell radiosensitivity and abrogation of G2 and S phase arrest by the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin.[J]. Clinical Cancer Research, 2004, 10 23: 8077-8084. DOI:
10.1158/1078-0432.ccr-04-1212[3] TONY TALDONE Gabriela C Weilin Sun. Discovery and development of heat shock protein 90 inhibitors[J]. Bioorganic & Medicinal Chemistry, 2009, 17 6: Pages 2225-2235. DOI:
10.1016/j.bmc.2008.10.087[4] CHRISTINA HACKL. Activating transcription factor-3 (ATF3) functions as a tumor suppressor in colon cancer and is up-regulated upon heat-shock protein 90 (Hsp90) inhibition.[J]. BMC Cancer, 2010, 10: 668. DOI:
10.1186/1471-2407-10-668[5] RAMESH K RAMANATHAN. Phase I pharmacokinetic and pharmacodynamic study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors.[J]. Journal of Clinical Oncology, 2010, 28 9: 1520-1526. DOI:
10.1200/jco.2009.25.0415[6] NARUYUKI KOBAYASHI . The anti-proliferative effect of heat shock protein 90 inhibitor, 17-DMAG, on non-small-cell lung cancers being resistant to EGFR tyrosine kinase inhibitor[J]. Lung Cancer, 2012, 75 2: Pages 161-166. DOI:
10.1016/j.lungcan.2011.04.022[7] JULIO MADRIGAL-MATUTE. Heat shock protein 90 inhibitors attenuate inflammatory responses in atherosclerosis.[J]. Cardiovascular Research, 2010, 86 2: 330-337. DOI:
10.1093/cvr/cvq046[8] SAMUEL K SHIMP. HSP90 inhibition by 17-DMAG reduces inflammation in J774 macrophages through suppression of Akt and nuclear factor-κB pathways.[J]. Inflammation Research, 2012, 61 5: 521-533. DOI:
10.1007/s00011-012-0442-x[9] HONG-MEI ZHANG. Geldanamycin derivative ameliorates high fat diet-induced renal failure in diabetes.[J]. PLoS ONE, 2012: e32746. DOI:
10.1371/journal.pone.0032746
