Discovery of benzamide tetrahydro-4H-carbazol-4-ones as novel small molecule inhibitors of Hsp90.
Hsp90 maintains the conformational stability of multiple proteins implicated in oncogenesis and has emerged as a target for chemotherapy. We report here the discovery of a novel small molecule scaffold that inhibits Hsp90. X-ray data show that the scaffold binds competitively at the ATP site on Hsp90. Cellular proliferation and client assays demonstrate that members of the series are able to inhibit Hsp90 at nanomolar concentrations.
Serenex, Inc., 323 Foster St., Durham, NC 27701, USA.
Thomas E
TE
Barta
James M
JM
Veal
John W
JW
Rice
Jeffrey M
JM
Partridge
R Patrick
RP
Fadden
Wei
W
Ma
Matthew
M
Jenks
Lifeng
L
Geng
Gunnar J
GJ
Hanson
Kenneth H
KH
Huang
Amy F
AF
Barabasz
Briana E
BE
Foley
James
J
Otto
Steven E
SE
Hall
D000255:Adenosine Triphosphate / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002227:Carbazoles; D018841:HSP90 Heat-Shock Proteins; D054852:Small Molecule Libraries; D000255:Adenosine Triphosphate