Structure-based drug design of novel ASK1 inhibitors using an integrated lead optimization strategy

Bioorg Med Chem Lett. 2017 Apr 15;27(8):1709-1713. doi: 10.1016/j.bmcl.2017.02.079. Epub 2017 Mar 2.


Structure-based drug design is an iterative process that is an established means to accelerate lead optimization, and is most powerful when integrated with information from different sources. Herein is described the use of such methods in conjunction with deconstruction and re-optimization of a diverse series of ASK1 chemotypes along with high-throughput screening that lead to the identification of a novel series of efficient ASK1 inhibitors displaying robust MAP3K pathway inhibition.

Keywords: Apoptosis signal-regulating kinase 1 (ASK1); Structure-based drug design (SBDD).

MeSH terms

  • Drug Design*
  • Drug Evaluation, Preclinical
  • High-Throughput Screening Assays
  • Humans
  • MAP Kinase Kinase Kinase 5 / antagonists & inhibitors*
  • MAP Kinase Kinase Kinase 5 / chemistry
  • MAP Kinase Kinase Kinase 5 / metabolism
  • MAP Kinase Signaling System / drug effects
  • Molecular Docking Simulation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*


  • Protein Kinase Inhibitors
  • MAP Kinase Kinase Kinase 5