title: Design, synthesis, and biological evaluation of hydroquinone derivatives of 17-amino-17-demethoxygeldanamycin as potent, water-soluble inhibitors of Hsp90.
abstract: 17-Allylamino-17-demethoxygeldanamycin (17-AAG)1 is a semisynthetic inhibitor of the 90 kDa heat shock protein (Hsp90) currently in clinical trials for the treatment of cancer. However, 17-AAG faces challenging formulation issues due to its poor solubility. Here we report the synthesis and evaluation of a highly soluble hydroquinone hydrochloride derivative of 17-AAG, 1a (IPI-504), and several of the physiological metabolites. These compounds show comparable binding affinity to human Hsp90 and its endoplasmic reticulum (ER) homologue, the 94 kDa glucose regulated protein (Grp94). Furthermore, the compounds inhibit the growth of the human cancer cell lines SKBR3 and SKOV3, which overexpress Hsp90 client protein Her2, and cause down-regulation of Her2 as well as induction of Hsp70 consistent with Hsp90 inhibition. There is a clear correlation between the measured binding affinity of the compounds and their cellular activities. Upon the basis of its potent activity against Hsp90 and a significant improvement in solubility, 1a is currently under evaluation in Phase I clinical trials for cancer.
authors.affiliation: Infinity Pharmaceuticals, Inc., 780 Memorial Drive, Cambridge, Massachusetts 02139, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Ge
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Normant
authors.forename: James R
authors.initials: JR
authors.lastname: Porter
authors.forename: Janid A
authors.initials: JA
authors.lastname: Ali
authors.forename: Marlene S
authors.initials: MS
authors.lastname: Dembski
authors.forename: Yun
authors.initials: Y
authors.lastname: Gao
authors.forename: Asimina T
authors.initials: AT
authors.lastname: Georges
authors.forename: Louis
authors.initials: L
authors.lastname: Grenier
authors.forename: Roger H
authors.initials: RH
authors.lastname: Pak
authors.forename: Jon
authors.initials: J
authors.lastname: Patterson
authors.forename: Jens R
authors.initials: JR
authors.lastname: Sydor
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Tibbitts
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Tong
authors.forename: Julian
authors.initials: J
authors.lastname: Adams
authors.forename: Vito J
authors.initials: VJ
authors.lastname: Palombella
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016227:Benzoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D004285:Dogs; D004354:Drug Screening Assays, Antitumor; D005454:Fluorescence Polarization; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis / Q000737:chemistry; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D006873:Hydroquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry; D008958:Models, Molecular; D020033:Protein Isoforms / Q000737:chemistry; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D017828:Rifabutin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
chemical_list: D000970:Antineoplastic Agents; D016227:Benzoquinones; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D006873:Hydroquinones; D047029:Lactams, Macrocyclic; D008565:Membrane Proteins; D020033:Protein Isoforms; D018719:Erb-b2 Receptor Tyrosine Kinases; D017828:Rifabutin; D014867:Water; C018551:glucose-regulated proteins; C112765:tanespimycin