High throughput discovery of heteroaromatic-modifying enzymes allows enhancement of novobiocin selectivity

Chem Commun (Camb). 2011 Oct 14;47(38):10569-71. doi: 10.1039/c1cc13552j. Epub 2011 Aug 24.

Abstract

Glycosylated analogues of novobiocin, discovered using a broad library of enzymes, have 100-fold improved activity against breast, brain, pancreatic, lung and ovarian cancers and ablated associated off-target activity leading to an up to 2.7 × 10(4) fold increase in selectivity.

MeSH terms

  • Cell Line, Tumor
  • DNA Topoisomerases, Type II / chemistry
  • DNA Topoisomerases, Type II / metabolism
  • Drug Screening Assays, Antitumor
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / toxicity
  • Enzymes / chemistry*
  • Enzymes / metabolism
  • Glycosylation / drug effects
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors
  • HSP90 Heat-Shock Proteins / metabolism
  • Humans
  • Novobiocin / chemical synthesis
  • Novobiocin / chemistry*
  • Novobiocin / toxicity

Substances

  • Enzyme Inhibitors
  • Enzymes
  • HSP90 Heat-Shock Proteins
  • Novobiocin
  • DNA Topoisomerases, Type II