Adenine derived inhibitors of the molecular chaperone HSP90-SAR explained through multiple X-ray structures.
Multiple co-crystal structures of an adenine-based series of inhibitors bound to the molecular chaperone Hsp90 have been determined. These structures explain the observed SAR for previously described compounds and new compounds, which possess up to 8-fold improved potency against the isolated enzyme. Anti-tumour cell potency and mechanism of action data is also described for the most potent compounds. These data should enable the design of more potent Hsp90 inhibitors.
Dymock
Brian
B
RiboTargets Ltd, Granta Park, CB1 6GB, Cambridge, UK. b.dymock@ribotargets.com
Barril
Xavier
X
Beswick
Mandy
M
Collier
Adam
A
Davies
Nicholas
N
Drysdale
Martin
M
Fink
Alexandra
A
Fromont
Christophe
C
Hubbard
Roderick E
RE
Massey
Andrew
A
Surgenor
Allan
A
Wright
Lisa
L
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship
D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; D000225:Adenine