Combining hit identification strategies: fragment-based and in silico approaches to orally active 2-aminothieno[2,3-d]pyrimidine inhibitors of the Hsp90 molecular chaperone.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential molecular therapeutic agents for the treatment of cancer. Here we describe novel 2-aminothieno[2,3-d]pyrimidine ATP competitive Hsp90 inhibitors, which were designed by combining structural elements of distinct low affinity hits generated from fragment-based and in silico screening exercises in concert with structural information from X-ray protein crystallography. Examples from this series have high affinity (IC50 = 50-100 nM) for Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Several examples (34a, 34d and 34i) caused tumor growth regression at well tolerated doses when administered orally in a human BT474 human breast cancer xenograft model.
Brough
Paul A
PA
Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, UK. p.brough@vernalis.com
Barril
Xavier
X
Borgognoni
Jenifer
J
Chene
Patrick
P
Davies
Nicholas G M
NG
Davis
Ben
B
Drysdale
Martin J
MJ
Dymock
Brian
B
Eccles
Suzanne A
SA
Garcia-Echeverria
Carlos
C
Fromont
Christophe
C
Hayes
Angela
A
Hubbard
Roderick E
RE
Jordan
Allan M
AM
Jensen
Michael Rugaard
MR
Massey
Andrew
A
Merrett
Angela
A
Padfield
Antony
A
Parsons
Rachel
R
Radimerski
Thomas
T
Raynaud
Florence I
FI
Robertson
Alan
A
Roughley
Stephen D
SD
Schoepfer
Joseph
J
Simmonite
Heather
H
Sharp
Swee Y
SY
Surgenor
Allan
A
Valenti
Melanie
M
Walls
Steven
S
Webb
Paul
P
Wood
Mike
M
Workman
Paul
P
Wright
Lisa
L
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001667:Binding, Competitive; D018360:Crystallography, X-Ray; D005260:Female; D005454:Fluorescence Polarization; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D011743:Pyrimidines