Novel, potent small-molecule inhibitors of the molecular chaperone Hsp90 discovered through structure-based design.
The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmacodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.
Vernalis Ltd., Granta Park, Great Abington, Cambridge, UK.
Brian W
BW
Dymock
Xavier
X
Barril
Paul A
PA
Brough
Julie E
JE
Cansfield
Andrew
A
Massey
Edward
E
McDonald
Roderick E
RE
Hubbard
Allan
A
Surgenor
Stephen D
SD
Roughley
Paul
P
Webb
Paul
P
Workman
Lisa
L
Wright
Martin J
MJ
Drysdale
D000255:Adenosine Triphosphate / Q000378:metabolism; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D015195:Drug Design; D005998:Glycine; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D013329:Structure-Activity Relationship
D000577:Amides; D000588:Amines; D018841:HSP90 Heat-Shock Proteins; D000255:Adenosine Triphosphate; D005998:Glycine