4-Amino derivatives of the Hsp90 inhibitor CCT018159.
Novel piperazinyl, morpholino and piperidyl derivatives of the pyrazole-based Hsp90 inhibitor CCT018159 are described. Structure-activity relationships have been elucidated by X-ray co-crystal analysis of the new compounds bound to the N-terminal domain of human Hsp90. Key features of the binding mode are essentially identical to the recently reported potent analogue VER-49009. The most potent of the new compounds has a methylsulfonylbenzyl substituent appended to the piperazine nitrogen, possesses an IC50 of less than 600 nM binding against the enzyme and demonstrates low micromolar inhibition of tumour cell proliferation.
Vernalis Ltd, Granta Park, Cambridge CB1 6GB, UK.
Xavier
X
Barril
Mandy C
MC
Beswick
Adam
A
Collier
Martin J
MJ
Drysdale
Brian W
BW
Dymock
Alexandra
A
Fink
Kate
K
Grant
Robert
R
Howes
Allan M
AM
Jordan
Andrew
A
Massey
Allan
A
Surgenor
Joanne
J
Wayne
Paul
P
Workman
Lisa
L
Wright
D001665:Binding Sites; D018360:Crystallography, X-Ray; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
C506244:CCT018159; D018841:HSP90 Heat-Shock Proteins; D006574:Heterocyclic Compounds, 2-Ring; D011720:Pyrazoles