Discovery of novel 20S proteasome inhibitors by rational topology-based scaffold hopping of bortezomib

Bioorg Med Chem Lett. 2018 Jul 1;28(12):2148-2152. doi: 10.1016/j.bmcl.2018.05.018. Epub 2018 May 9.

Abstract

A series of structurally novel proteasome inhibitors 1-12 have been developed based rational topology-based scaffold hopping of bortezomib. Among these novel proteasome inhibitors, compound 10 represents an important advance due to the comparable proteasome-inhibitory activity (IC50 = 9.7 nM) to bortezomib (IC50 = 8.3 nM), the remarkably higher BEI and SEI values and the effectiveness in metabolic stability. Therefore, compound 10 provides an excellent lead suitable for further optimization.

Keywords: Bortezomib; Proteasome inhibitors; Scaffold hopping; Topology-based.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Bortezomib / chemical synthesis
  • Bortezomib / chemistry
  • Bortezomib / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemical synthesis
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Structure-Activity Relationship

Substances

  • Proteasome Inhibitors
  • Bortezomib
  • Proteasome Endopeptidase Complex