N-aryl-benzimidazolones as novel small molecule HSP90 inhibitors

Milan Bruncko; 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

doi:10.1016/j.bmcl.2010.10.010

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. Epub 2010 Oct 12.

Authors

Milan Bruncko¹, 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

Affiliation

¹ Cancer Research, Global Pharmaceutical R&D, Abbott Laboratories, Abbott Park, IL 60064-6101, USA. milan.bruncko@abbott.com

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.

MeSH terms

Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry*
Benzimidazoles / pharmacology
Binding Sites
Cell Line, Tumor
Crystallography, X-Ray
HSP90 Heat-Shock Proteins / antagonists & inhibitors*
HSP90 Heat-Shock Proteins / metabolism
Humans
Protein Structure, Tertiary
Structure-Activity Relationship

Substances

Benzimidazoles
HSP90 Heat-Shock Proteins
benzimidazolone