Strategies for stalling malignancy: targeting cancer's addiction to Hsp90.
Hsp90 is involved in the maturation and activation of client proteins. Often these are key proteins involved in signal transduction and regulatory pathways that in a mutated and/or deregulated form sustain an oncogenic cellular state. Consequently, the malignancy is maintained with the aid of Hsp90 upon which the mutated proteins have become particularly dependent for their activity. The requirement for the Hsp90 chaperone machine to drive the malignancy makes Hsp90 a prime anticancer target, an 'axle in a wheel' that when disrupted has been shown to be effective in killing cancerous cells. This review aims to identify potential drug targets, based on the current structural knowledge of the Hsp90-chaperone machine, that could be targeted with the aim of disrupting its functioning and promoting an anti-cancer activity.
Section of Structural Biology, The Institute of Cancer Research, Chester Beatty Laboratories, London SW3 6JB, UK. chris.prodromou@icr.ac.uk
Chrisostomos
C
Prodromou
D000251:Adenosine Triphosphatases / Q000737:chemistry / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism*; D011487:Protein Conformation / Q000187:drug effects
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases