Novel adenosine-derived inhibitors of 70 kDa heat shock protein, discovered through structure-based design.
The design and synthesis of novel adenosine-derived inhibitors of HSP70, guided by modeling and X-ray crystallographic structures of these compounds in complex with HSC70/BAG-1, is described. Examples exhibited submicromolar affinity for HSP70, were highly selective over HSP90, and some displayed potency against HCT116 cells. Exposure of compound 12 to HCT116 cells caused significant reduction in cellular levels of Raf-1 and Her2 at concentrations similar to that which caused cell growth arrest.
Williamson
Douglas S
DS
Vernalis (R&D) Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, United Kingdom. d.williamson@vernalis.com
Borgognoni
Jenifer
J
Clay
Alexandra
A
Daniels
Zoe
Z
Dokurno
Pawel
P
Drysdale
Martin J
MJ
Foloppe
Nicolas
N
Francis
Geraint L
GL
Graham
Christopher J
CJ
Howes
Rob
R
Macias
Alba T
AT
Murray
James B
JB
Parsons
Rachel
R
Shaw
Terry
T
Surgenor
Allan E
AE
Terry
Lindsey
L
Wang
Yikang
Y
Wood
Mike
M
Massey
Andrew J
AJ
D000241:Adenosine / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D016231:Fluorescence Polarization Immunoassay; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D015394:Molecular Structure
D018840:HSP70 Heat-Shock Proteins; D000241:Adenosine