title: The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors.
abstract: High-throughput screening identified the 3,4-diarylpyrazole CCT018159 as a novel and potent (7.1 microM) inhibitor of Hsp90 ATPase activity. Here, we describe the synthesis of CCT018159 and a number of close analogues together with data on their biochemical properties. Some initial structure-activity relationships are discussed, as well as the crystal structure of CCT018159 bound to Hsp90.
authors.affiliation: Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Cancer Research UK and Haddow Laboratories, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK.
authors.forename: Kwai-Ming J
authors.initials: KM
authors.lastname: Cheung
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Matthews
authors.forename: Karen
authors.initials: K
authors.lastname: James
authors.forename: Martin G
authors.initials: MG
authors.lastname: Rowlands
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Boxall
authors.forename: Swee Y
authors.initials: SY
authors.lastname: Sharp
authors.forename: Alison
authors.initials: A
authors.lastname: Maloney
authors.forename: S Mark
authors.initials: SM
authors.lastname: Roe
authors.forename: Chrisostomos
authors.initials: C
authors.lastname: Prodromou
authors.forename: Laurence H
authors.initials: LH
authors.lastname: Pearl
authors.forename: G Wynne
authors.initials: GW
authors.lastname: Aherne
authors.forename: Edward
authors.initials: E
authors.lastname: McDonald
authors.forename: Paul
authors.initials: P
authors.lastname: Workman
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000737:chemistry / Q000201:enzymology
chemical_list: C506244:CCT018159; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D006574:Heterocyclic Compounds, 2-Ring; D011720:Pyrazoles; D000251:Adenosine Triphosphatases