title: Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy.
abstract: Targeted inhibition of the molecular chaperone Hsp90 results in the simultaneous blockade of multiple oncogenic signaling pathways and has, thus, emerged as an attractive strategy for the development of novel cancer therapeutics. Ganetespib (formerly known as STA-9090) is a unique resorcinolic triazolone inhibitor of Hsp90 that is currently in clinical trials for a number of human cancers. In the present study, we showed that ganetespib exhibits potent in vitro cytotoxicity in a range of solid and hematologic tumor cell lines, including those that express mutated kinases that confer resistance to small-molecule tyrosine kinase inhibitors. Ganetespib treatment rapidly induced the degradation of known Hsp90 client proteins, displayed superior potency to the ansamycin inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), and exhibited sustained activity even with short exposure times. In vivo, ganetespib showed potent antitumor efficacy in solid and hematologic xenograft models of oncogene addiction, as evidenced by significant growth inhibition and/or regressions. Notably, evaluation of the microregional activity of ganetespib in tumor xenografts showed that ganetespib was efficiently distributed throughout tumor tissue, including hypoxic regions >150 μm from the microvasculature, to inhibit proliferation and induce apoptosis. Importantly, ganetespib showed no evidence of cardiac or liver toxicity. Taken together, this preclinical activity profile indicates that ganetespib may have broad application for a variety of human malignancies, and with select mechanistic and safety advantages over other first- and second-generation Hsp90 inhibitors.
authors.affiliation: Synta Pharmaceuticals Corp., 45 Hartwell Avenue, Lexington, MA 02421, USA. wying@syntapharma.com
authors.forename: Weiwen
authors.initials: W
authors.lastname: Ying
authors.forename: Zhenjian
authors.initials: Z
authors.lastname: Du
authors.forename: Lijun
authors.initials: L
authors.lastname: Sun
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Foley
authors.forename: David A
authors.initials: DA
authors.lastname: Proia
authors.forename: Ronald K
authors.initials: RK
authors.lastname: Blackman
authors.forename: Dan
authors.initials: D
authors.lastname: Zhou
authors.forename: Takayo
authors.initials: T
authors.lastname: Inoue
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tatsuta
authors.forename: Jim
authors.initials: J
authors.lastname: Sang
authors.forename: Shuxia
authors.initials: S
authors.lastname: Ye
authors.forename: Jamie
authors.initials: J
authors.lastname: Acquaviva
authors.forename: Luisa Shin
authors.initials: LS
authors.lastname: Ogawa
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Wada
authors.forename: James
authors.initials: J
authors.lastname: Barsoum
authors.forename: Keizo
authors.initials: K
authors.lastname: Koya
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016227:Benzoquinones / Q000009:adverse effects / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D018360:Crystallography, X-Ray; D005260:Female; D018922:HL-60 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020014:K562 Cells; D047029:Lactams, Macrocyclic / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C533237:STA 9090; D014230:Triazoles; C112765:tanespimycin