3-(5-Chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as inhibitors of the Hsp90 molecular chaperone.
Information from X-ray crystal structures of Hsp90 inhibitors bound to the human Hsp90 molecular chaperone was used to assist in the design of 3-(5-chloro-2,4-dihydroxyphenyl)-pyrazole-4-carboxamides as novel inhibitors of Hsp90. Accessing an extra interaction with the protein via Phe138 gave a significant increase in binding potency compared to similar analogues that do not make this interaction.
Brough
Paul A
PA
Vernalis Ltd, Granta Park, Great Abington, Cambridge CB1 6GB, UK. p.brough@vernalis.com
Barril
Xavier
X
Beswick
Mandy
M
Dymock
Brian W
BW
Drysdale
Martin J
MJ
Wright
Lisa
L
Grant
Kate
K
Massey
Andrew
A
Surgenor
Allan
A
Workman
Paul
P
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure; D010072:Oxamic Acid / Q000737:chemistry; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology
D000577:Amides; D018841:HSP90 Heat-Shock Proteins; D011720:Pyrazoles; D010072:Oxamic Acid