title: Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents.
abstract: 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.
authors: Serenex Inc, Durham, North Carolina 27701, USA. khuang@pamlicopharma.com
authors: Kenneth H
authors: KH
authors: Huang
authors: James M
authors: JM
authors: Veal
authors: R Patrick
authors: RP
authors: Fadden
authors: John W
authors: JW
authors: Rice
authors: Jeron
authors: J
authors: Eaves
authors: Jon-Paul
authors: JP
authors: Strachan
authors: Amy F
authors: AF
authors: Barabasz
authors: Briana E
authors: BE
authors: Foley
authors: Thomas E
authors: TE
authors: Barta
authors: Wei
authors: W
authors: Ma
authors: Melanie A
authors: MA
authors: Silinski
authors: Mei
authors: M
authors: Hu
authors: Jeffrey M
authors: JM
authors: Partridge
authors: Anisa
authors: A
authors: Scott
authors: Laura G
authors: LG
authors: DuBois
authors: Tiffany
authors: T
authors: Freed
authors: Paul M
authors: PM
authors: Steed
authors: Andy J
authors: AJ
authors: Ommen
authors: Emilie D
authors: ED
authors: Smith
authors: Philip F
authors: PF
authors: Hughes
authors: Angela R
authors: AR
authors: Woodward
authors: Gunnar J
authors: GJ
authors: Hanson
authors: W Stephen
authors: WS
authors: McCall
authors: Christopher J
authors: CJ
authors: Markworth
authors: Lindsay
authors: L
authors: Hinkley
authors: Matthew
authors: M
authors: Jenks
authors: Lifeng
authors: L
authors: Geng
authors: Meredith
authors: M
authors: Lewis
authors: James
authors: J
authors: Otto
authors: Bert
authors: B
authors: Pronk
authors: Katleen
authors: K
authors: Verleysen
authors: Steven E
authors: SE
authors: Hall
mesh_terms: 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*
chemical_list: 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