Geldanamycin and its derivatives as Hsp90 inhibitors.
The Hsp90 molecule, one of the most abundant heat shock proteins in mammalian cells, maintains homeostasis and prevents stress-induced cellular damage. Hsp90 is expressed under normal conditions at a level of about 1-2 Percent of total proteins, while its expression increases 2-10 fold in cancer cells. The two main constitutively expressed isoforms of Hsp90 are known as Hsp90-alpha and Hsp90-beta, and their upregulation is associated with tumor progression, invasion and formation of metastases, as well as development of drug resistance. The Hsp90 is a key target for many newly established, potent anticancer agents containing Hsp90 N-terminal ATP binding inhibitors, such as geldanamycin, and its analogues 17AAG and 17DMAG. The therapeutic usage of geldanamycin has been limited due to its poor water solubility and severe hepatotoxicity. Therefore, its analogues, including 17AAG, 17DMAG, Tanespimycin and Retaspimycin hydrochloride, with improved pharmacokinetic profiles, have been developed.
Department of Medical Chemistry, Medical University of Gdansk, Gdansk, Poland. m.gorska@gumed.edu.pl
Magdalena
M
Gorska
Urszula
U
Popowska
Alicja
A
Sielicka-Dudzin
Alicja
A
Kuban-Jankowska
Wojciech
W
Sawczuk
Narcyz
N
Knap
Giuseppe
G
Cicero
Fabio
F
Wozniak
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007211:Indoles; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology*; D018942:Macrolides / Q000494:pharmacology; D008954:Models, Biological; D009154:Mutation; D009675:Novobiocin / Q000494:pharmacology; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D047029:Lactams, Macrocyclic; D018942:Macrolides; C533237:STA 9090; D016212:Transforming Growth Factor beta; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D009675:Novobiocin; C545221:STA-1474; D019061:src-Family Kinases; D019908:Proto-Oncogene Proteins c-raf; D018844:Cyclin-Dependent Kinases; C035359:monorden; C001277:geldanamycin