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: Kenneth H Huang, James M Veal, R Patrick Fadden, John W Rice, Jeron Eaves, Jon-Paul Strachan, Amy F Barabasz, Briana E Foley, Thomas E Barta, Wei Ma, Melanie A Silinski, Mei Hu, Jeffrey M Partridge, Anisa Scott, Laura G DuBois, Tiffany Freed, Paul M Steed, Andy J Ommen, Emilie D Smith, Philip F Hughes, Angela R Woodward, Gunnar J Hanson, W Stephen McCall, Christopher J Markworth, Lindsay Hinkley, Matthew Jenks, Lifeng Geng, Meredith Lewis, James Otto, Bert Pronk, Katleen Verleysen, Steven E Hall
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 52 Issue 14 Pg. 4288-305 (Jul 23 2009) ISSN: 1520-4804 [Electronic] United States
• PMID: 19552433 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• HSP90 Heat-Shock Proteins
• Heterocyclic Compounds, 4 or More Rings
• Prodrugs
• SNX 2112
• ortho-Aminobenzoates
• anthranilamide

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Biological Availability
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Clinical Trials as Topic
• Drug Discovery
• Female
• HSP90 Heat-Shock Proteins (antagonists & inhibitors)
• Heterocyclic Compounds, 4 or More Rings (chemistry, pharmacokinetics, pharmacology)
• Humans
• Inhibitory Concentration 50
• Mice
• Models, Molecular
• Molecular Conformation
• Prodrugs (pharmacokinetics)
• Substrate Specificity
• ortho-Aminobenzoates (administration & dosage, chemistry, pharmacokinetics, pharmacology)