title: The heat shock protein 90 inhibitor, AT13387, displays a long duration of action in vitro and in vivo in non-small cell lung cancer.
abstract: A ubiquitously expressed chaperone, heat shock protein 90 (HSP90) is of considerable interest as an oncology target because tumor cells and oncogenic proteins are acutely dependent on its activity. AT13387 (2,4-dihydroxy-5-isopropyl-phenyl)-[5-(4-methyl-piperazin-1-ylmethyl)-1,3-dihydro-isoindol-2-yl] methanone, l-lactic acid salt) a novel, high-affinity HSP90 inhibitor, which is currently being clinically tested, has shown activity against a wide array of tumor cell lines, including lung cancer cell lines. This inhibitor has induced the degradation of specific HSP90 client proteins for up to 7 days in tumor cell lines in vitro. The primary driver of cell growth (mutant epidermal growth factor receptors) was particularly sensitive to HSP90 inhibition. The long duration of client protein knockdown and suppression of phospho-signaling seen in vitro after treatment with AT13387 was also apparent in vivo, with client proteins and phospho-signaling suppressed for up to 72 h in xenograft tumors after treatment with a single dose of AT13387. Pharmacokinetic analyses indicated that while AT13387 was rapidly cleared from blood, its retention in tumor xenografts was markedly extended, and it was efficacious in a range of xenograft models. AT13387's long duration of action enabled, in particular, its efficacious once weekly administration in human lung carcinoma xenografts. The use of longer-acting HSP90 inhibitors, such as AT13387, on less frequent dosing regimens has the potential to maintain antitumor efficacy as well as minimize systemic exposure and unwanted effects on normal tissues.
authors.affiliation: Astex Pharmaceuticals Ltd., Cambridge, UK. Brent.Graham@astx.com
authors.forename: Brent
authors.initials: B
authors.lastname: Graham
authors.forename: Jayne
authors.initials: J
authors.lastname: Curry
authors.forename: Tomoko
authors.initials: T
authors.lastname: Smyth
authors.forename: Lynsey
authors.initials: L
authors.lastname: Fazal
authors.forename: Ruth
authors.initials: R
authors.lastname: Feltell
authors.forename: Isobel
authors.initials: I
authors.lastname: Harada
authors.forename: Joe
authors.initials: J
authors.lastname: Coyle
authors.forename: Brian
authors.initials: B
authors.lastname: Williams
authors.forename: Matthias
authors.initials: M
authors.lastname: Reule
authors.forename: Hayley
authors.initials: H
authors.lastname: Angove
authors.forename: David M
authors.initials: DM
authors.lastname: Cross
authors.forename: John
authors.initials: J
authors.lastname: Lyons
authors.forename: Nicola G
authors.initials: NG
authors.lastname: Wallis
authors.forename: Neil T
authors.initials: NT
authors.lastname: Thompson
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D054833:Isoindoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018841:HSP90 Heat-Shock Proteins; D054833:Isoindoles; C552103:(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone