Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents.
A novel class of heat shock protein 90 (Hsp90) inhibitors was developed from an unbiased screen to identify protein targets for a diverse compound library. These indol-4-one and indazol-4-one derived 2-aminobenzamides showed strong binding affinity to Hsp90, and optimized analogues exhibited nanomolar antiproliferative activity across multiple cancer cell lines. Heat shock protein 70 (Hsp70) induction and specific client protein degradation in cells on treatment with the inhibitors supported Hsp90 inhibition as the mechanism of action. Computational chemistry and X-ray crystallographic analysis of selected member compounds clearly defined the protein-inhibitor interaction and assisted the design of analogues. 4-[6,6-Dimethyl-4-oxo-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]-2-[(trans-4-hydroxycyclohexyl)amino]benzamide (SNX-2112, 9) was identified as highly selective and potent (IC(50) Her2 = 11 nM, HT-29 = 3 nM); its prodrug amino-acetic acid 4-[2-carbamoyl-5-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-phenylamino]-cyclohexyl ester methanesulfonate (SNX-5422, 10) was orally bioavailable and efficacious in a broad range of xenograft tumor models (e.g. 67% growth delay in a HT-29 model) and is now in multiple phase I clinical trials.
Huang
Kenneth H
KH
Serenex Inc, Durham, North Carolina 27701, USA. khuang@pamlicopharma.com
Veal
James M
JM
Fadden
R Patrick
RP
Rice
John W
JW
Eaves
Jeron
J
Strachan
Jon-Paul
JP
Barabasz
Amy F
AF
Foley
Briana E
BE
Barta
Thomas E
TE
Ma
Wei
W
Silinski
Melanie A
MA
Hu
Mei
M
Partridge
Jeffrey M
JM
Scott
Anisa
A
DuBois
Laura G
LG
Freed
Tiffany
T
Steed
Paul M
PM
Ommen
Andy J
AJ
Smith
Emilie D
ED
Hughes
Philip F
PF
Woodward
Angela R
AR
Hanson
Gunnar J
GJ
McCall
W Stephen
WS
Markworth
Christopher J
CJ
Hinkley
Lindsay
L
Jenks
Matthew
M
Geng
Lifeng
L
Lewis
Meredith
M
Otto
James
J
Pronk
Bert
B
Verleysen
Katleen
K
Hall
Steven E
SE
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D055808:Drug Discovery; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D011355:Prodrugs / Q000493:pharmacokinetics; D013379:Substrate Specificity; D062367:ortho-Aminobenzoates / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
D000970:Antineoplastic Agents; D018841:HSP90 Heat-Shock Proteins; D006576:Heterocyclic Compounds, 4 or More Rings; D011355:Prodrugs; C534922:SNX 2112; D062367:ortho-Aminobenzoates; C000219:anthranilamide