title: 7'-substituted benzothiazolothio- and pyridinothiazolothio-purines as potent heat shock protein 90 inhibitors.
abstract: We report on the discovery of benzo- and pyridino- thiazolothiopurines as potent heat shock protein 90 inhibitors. The benzothiazole moiety is exceptionally sensitive to substitutions on the aromatic ring with a 7'-substituent essential for activity. Some of these compounds exhibit low nanomolar inhibition activity in a Her-2 degradation assay (28-150 nM), good aqueous solubility, and oral bioavailability profiles in mice. In vivo efficacy experiments demonstrate that compounds of this class inhibit tumor growth in an N87 human colon cancer xenograft model via oral administration as shown with compound 37 (8-(7-chlorobenzothiazol-2-ylsulfanyl)-9-(2-cyclopropylamino-ethyl)-9H- purin-6-ylamine).
authors.affiliation: Department of Medicinal Chemistry, Conforma Therapeutics Corporation, 9393 Towne Centre Drive, Suite 240, San Diego, California 92121, USA. lzhang@conformacorp.com
authors.forename: Lin
authors.initials: L
authors.lastname: Zhang
authors.forename: Junhua
authors.initials: J
authors.lastname: Fan
authors.forename: Khang
authors.initials: K
authors.lastname: Vu
authors.forename: Kevin
authors.initials: K
authors.lastname: Hong
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Le Brazidec
authors.forename: Jiandong
authors.initials: J
authors.lastname: Shi
authors.forename: Marco
authors.initials: M
authors.lastname: Biamonte
authors.forename: David J
authors.initials: DJ
authors.lastname: Busch
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Lough
authors.forename: Roy
authors.initials: R
authors.lastname: Grecko
authors.forename: Yingqing
authors.initials: Y
authors.lastname: Ran
authors.forename: John L
authors.initials: JL
authors.lastname: Sensintaffar
authors.forename: Adeela
authors.initials: A
authors.lastname: Kamal
authors.forename: Karen
authors.initials: K
authors.lastname: Lundgren
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Burrows
authors.forename: Robert
authors.initials: R
authors.lastname: Mansfield
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Timony
authors.forename: Edgar H
authors.initials: EH
authors.lastname: Ulm
authors.forename: Srinivas R
authors.initials: SR
authors.lastname: Kasibhatla
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Boehm
mesh_terms: D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D011687:Purines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013997:Time Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D018841:HSP90 Heat-Shock Proteins; D011687:Purines; D013438:Sulfhydryl Compounds