N-aryl-benzimidazolones as novel small molecule HSP90 inhibitors

  • Bioorg Med Chem Lett. 2010 Dec 15;20(24):7503-6. doi: 10.1016/j.bmcl.2010.10.010.
Milan Bruncko  1 ,  Stephen K Tahir ,  Xiaohong Song ,  Jun Chen ,  Hong Ding ,  Jeffrey R Huth ,  Sha Jin ,  Russell A Judge ,  David J Madar ,  Chang H Park ,  Cheol-Min Park ,  Andrew M Petros ,  Christin Tse ,  Saul H Rosenberg ,  Steven W Elmore
Affiliations
  • 1. Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. [email protected]
PMID: 21106457 DOI: 10.1016/j.bmcl.2010.10.010
Abstract

We describe the development of a novel series of N-aryl-benzimidazolone HSP90 inhibitors (9) targeting the N-terminal ATP-ase site. SAR development was influenced by structure-based design based around X-ray structures of ligand bound HSP90 complexes. Lead compounds exhibited high binding affinities, ATP-ase inhibition and cellular client protein degradation.