2. Academic Validation
  3. Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents

Discovery of novel 2-aminobenzamide inhibitors of heat shock protein 90 as potent, selective and orally active antitumor agents

  • J Med Chem. 2009 Jul 23;52(14):4288-305. doi: 10.1021/jm900230j.
Kenneth H Huang 1,  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
Affiliations

Affiliation

  • 1 Serenex Inc, Durham, North Carolina 27701, USA. khuang@pamlicopharma.com
PMID: 19552433 DOI: 10.1021/jm900230j
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.

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