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.
Barril
Xavier
X
Vernalis Ltd, Granta Park, Cambridge CB1 6GB, UK.
Beswick
Mandy C
MC
Collier
Adam
A
Drysdale
Martin J
MJ
Dymock
Brian W
BW
Fink
Alexandra
A
Grant
Kate
K
Howes
Robert
R
Jordan
Allan M
AM
Massey
Andrew
A
Surgenor
Allan
A
Wayne
Joanne
J
Workman
Paul
P
Wright
Lisa
L
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