Hsp90 inhibitors in the clinic.
Specific inhibitors of Hsp90 have recently entered human clinical trials. At the time of writing, trials have been initiated only in metastatic cancer, although a rationale exists for using these agents in a variety of human diseases where protein (mis)folding is involved in the disease pathophysiology. Hsp90 inhibitors offer a unique anti-cancer opportunity because they provide simultaneous combinatorial blockade of multiple oncogenic pathways. The first compound in this class, 17-AAG, has completed phase I trials and phase II trials are in progress. The toxicity has been manageable and evidence of possible clinical activity has been seen in metastatic melanoma, prostate cancer and multiple myeloma. Other inhibitors with improved properties are approaching clinical trials. This chapter presents an update of the current clinical trials using Hsp90 inhibitors, focussing on the areas that will be increasingly relevant in the next 5 years.
Pacey
S
S
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey.
Banerji
U
U
Judson
I
I
Workman
P
P
D016227:Benzoquinones; D002986:Clinical Trials as Topic; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D047029:Lactams, Macrocyclic; D008297:Male; D008545:Melanoma / Q000188:drug therapy; D009101:Multiple Myeloma / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011809:Quinones / Q000627:therapeutic use; D017828:Rifabutin / Q000031:analogs & derivatives / Q000627:therapeutic use
D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D017828:Rifabutin; C112765:tanespimycin