Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents
| Autor: | Jeron Eaves, Meredith Lewis, Steven E. Hall, Amy F. Barabasz, Mei Hu, Andy J. Ommen, James Marvin Veal, Barta Thomas E, James C. Otto, Matthew Jenks, Bert Pronk, Jeffrey M. Partridge, John W. Rice, Melanie Silinski, Katleen Verleysen, Lindsay Hinkley, Jon-Paul Strachan, Briana Foley, Angela R. Woodward, Geng Lifeng, Anisa Scott, Emilie D. Smith, Wei Ma, Paul M. Steed, Tiffany Freed, Laura G. Dubois, W. Stephen Mccall, Hanson Gunnar J, Philip F. Hughes, Patrick Fadden, Kenneth He Huang, Christopher John Markworth |
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| Rok vydání: | 2009 |
| Předmět: |
Models
Molecular Stereochemistry Molecular Conformation Administration Oral Biological Availability Antineoplastic Agents Protein degradation Heterocyclic Compounds 4 or More Rings Substrate Specificity chemistry.chemical_compound Inhibitory Concentration 50 Mice Heat shock protein Cell Line Tumor Drug Discovery medicine Animals Humans Prodrugs ortho-Aminobenzoates HSP90 Heat-Shock Proteins Benzamide Cell Proliferation Clinical Trials as Topic biology Prodrug Hsp90 Hsp70 Mechanism of action Biochemistry chemistry Chaperone (protein) biology.protein Molecular Medicine Female medicine.symptom |
| Zdroj: | Journal of medicinal chemistry. 52(14) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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