Altered states: selectively drugging the Hsp90 cancer chaperone.
The molecular chaperone Hsp90 is an exciting cancer drug target. The first Hsp90 inhibitor to enter clinical trials--the geldanamycin derivative 17AAG--has recently demonstrated proof-of-concept for successful target modulation, with sighs of therapeutic benefit. An important property of Hsp90 inhibitors is their ability to cause simultaneous, combinatorial blockade of multiple cancer-causing pathways by promoting the degradation of many oncogenic client proteins. However, the reason for therapeutic selectivity in cancer cells versus normal cells is unclear. New research now shows that Hsp90 exists in cancer cells in a heightened, activated state that is highly susceptible to inhibition by 17AAG.
Workman
Paul
P
Cancer Research UK Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, UK. paul.workman@icr.ac.uk
D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D016227:Benzoquinones; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic; D007783:Lactones / Q000378:metabolism / Q000494:pharmacology; D018942:Macrolides; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D011485:Protein Binding; D011809:Quinones / Q000378:metabolism* / Q000627:therapeutic use; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology*
D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D007783:Lactones; D018942:Macrolides; D015513:Oncogene Proteins; D011809:Quinones; D017828:Rifabutin; C112765:tanespimycin; C035359:monorden; C001277:geldanamycin