Design and synthesis of triple inhibitors of janus kinase (JAK), histone deacetylase (HDAC) and Heat Shock Protein 90 (HSP90)

Bioorg Med Chem Lett. 2018 May 1;28(8):1357-1362. doi: 10.1016/j.bmcl.2018.03.009. Epub 2018 Mar 3.

Abstract

Inhibition of multiple signaling pathways in a cancer cell with a single molecule could result in better therapies that are simpler to administer. Efficacy may be achieved with reduced potency against individual targets if there is synergy through multiple pathway inhibition. To achieve this, it is necessary to be able to build multi-component ligands by joining together key pharmacophores in a way which maintains sufficient activity against the individual pathways. In this work, designed triple inhibiting ligands are explored aiming to block three completely different target types: a kinase (JAK2), an epigenetic target (HDAC) and a chaperone (HSP90). Although these enzymes have totally different functions they are related through inter-dependent pathways in the developing cancer cell. Synthesis of several complex multi-inhibiting ligands are presented along with initial enzyme inhibition data against 3 biological target classes of interest. A lead compound, 47, was discovered which had low micromolar activity for all 3 targets. Further development of these complex trispecific designed multiple ligands could result in a 'transient drug', an alternative combination therapy for treating cancer mediated via a single molecule.

Keywords: HDAC; HSP90; Janus kinase; Multiple ligand; Transient drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Drug Design
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • Histone Deacetylase Inhibitors / chemical synthesis*
  • Histone Deacetylase Inhibitors / chemistry
  • Janus Kinase 2 / antagonists & inhibitors*
  • Nitriles
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Pyrazoles / chemistry
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Vorinostat / chemistry

Substances

  • Amides
  • HSP90 Heat-Shock Proteins
  • Histone Deacetylase Inhibitors
  • NVP-BEP800
  • Nitriles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Vorinostat
  • ruxolitinib
  • Janus Kinase 2