4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.
Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.
Brough
Paul A
PA
Vernalis Ltd., Granta Park, Great Abington, Cambridge CB21 6GB, U.K. p.brough@ vernalis.com
Aherne
Wynne
W
Barril
Xavier
X
Borgognoni
Jenifer
J
Boxall
Kathy
K
Cansfield
Julie E
JE
Cheung
Kwai-Ming J
KM
Collins
Ian
I
Davies
Nicholas G M
NG
Drysdale
Martin J
MJ
Dymock
Brian
B
Eccles
Suzanne A
SA
Finch
Harry
H
Fink
Alexandra
A
Hayes
Angela
A
Howes
Robert
R
Hubbard
Roderick E
RE
James
Karen
K
Jordan
Allan M
AM
Lockie
Andrea
A
Martins
Vanessa
V
Massey
Andrew
A
Matthews
Thomas P
TP
McDonald
Edward
E
Northfield
Christopher J
CJ
Pearl
Laurence H
LH
Prodromou
Chrisostomos
C
Ray
Stuart
S
Raynaud
Florence I
FI
Roughley
Stephen D
SD
Sharp
Swee Y
SY
Surgenor
Allan
A
Walmsley
D Lee
DL
Webb
Paul
P
Wood
Mike
M
Workman
Paul
P
Wright
Lisa
L
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001667:Binding, Competitive; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005454:Fluorescence Polarization; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D009368:Neoplasm Transplantation; D012118:Resorcinols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
C528044:5-(2,4-dihydroxy-5-isopropylphenyl)-4-(4-morpholin-4-ylmethylphenyl)isoxazole-3-carboxylic acid ethylamide; D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D007555:Isoxazoles; D012118:Resorcinols