title: 17AAG: low target binding affinity and potent cell activity--finding an explanation.
abstract: The ansamycin geldanamycin (GM) and its derivative, 17AAG, now in early clinical trials in cancer patients, have potent activity against several cancer cells at low nanomolar concentrations. The main target of these drugs is the molecular chaperone heat shock protein 90. Contrary to the high antitumor potency, the affinity of these drugs for the chaperone was determined to be approximately 1 microM. We propose that this difference can partly be explained by the physicochemical characteristics of the ansamycins. GM and 17AAG accumulate in cells, producing higher intracellular concentrations than expected. We conclude that although apparent activity for ansamycins can be seen at low nanomolar concentration, their real activity correlates with the heat shock protein 90 binding affinity and is in the low micromolar concentration range. We suggest that in the clinic, micromolar concentrations of 17AAG must accumulate in the tumor cells to achieve antitumor effects in patients comparable with ones achieved in tissue culture settings.
authors.affiliation: Program in Cell Biology and Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA. chiosisg@mskcc.org
authors.forename: Gabriela
authors.initials: G
authors.lastname: Chiosis
authors.forename: Henri
authors.initials: H
authors.lastname: Huezo
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Edward
authors.initials: E
authors.lastname: Mimnaugh
authors.forename: Luke
authors.initials: L
authors.lastname: Whitesell
authors.forename: Len
authors.initials: L
authors.lastname: Neckers
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology; D016227:Benzoquinones; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D047029:Lactams, Macrocyclic; D008297:Male; D013058:Mass Spectrometry; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011809:Quinones / Q000493:pharmacokinetics / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology; D013347:Subcellular Fractions; D014407:Tumor Cells, Cultured
chemical_list: D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; C112765:tanespimycin; D017346:Protein Serine-Threonine Kinases; C001277:geldanamycin