2. Academic Validation
  3. Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model

Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model

  • Bioorg Med Chem Lett. 2011 Jun 15;21(12):3627-31. doi: 10.1016/j.bmcl.2011.04.102.
Christoph W Zapf 1,  Jonathan D Bloom,  Jamie L McBean,  Russell G Dushin,  Jennifer M Golas,  Hao Liu,  Judy Lucas,  Frank Boschelli,  Erik Vogan,  Jeremy I Levin
Affiliations

Affiliation

  • 1 Medicinal Chemistry, Pfizer, Pearl River, NY 10965, United States. christoph.zapf@pfizer.com
PMID: 21605975 DOI: 10.1016/j.bmcl.2011.04.102
Abstract

A novel series of macrocyclic ortho-aminobenzamide HSP90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells. This compound showed prolonged Hsp90-inhibitory activity at least 24h post-administration consistent with elevated and prolonged exposure in the tumor. When studied in a xenograft model, the compound demonstrated significant suppression of tumor growth.

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