The identification, synthesis, protein crystal structure and in vitro biochemical evaluation of a new 3,4-diarylpyrazole class of Hsp90 inhibitors.
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.
Cheung
Kwai-Ming J
KM
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.
Matthews
Thomas P
TP
James
Karen
K
Rowlands
Martin G
MG
Boxall
Katherine J
KJ
Sharp
Swee Y
SY
Maloney
Alison
A
Roe
S Mark
SM
Prodromou
Chrisostomos
C
Pearl
Laurence H
LH
Aherne
G Wynne
GW
McDonald
Edward
E
Workman
Paul
P
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
C506244:CCT018159; D004791:Enzyme Inhibitors; D018841:HSP90 Heat-Shock Proteins; D006574:Heterocyclic Compounds, 2-Ring; D011720:Pyrazoles; D000251:Adenosine Triphosphatases