Merging of ruxolitinib and vorinostat leads to highly potent inhibitors of JAK2 and histone deacetylase 6 (HDAC6)

Bioorg Med Chem Lett. 2018 Aug 15;28(15):2636-2640. doi: 10.1016/j.bmcl.2018.06.037. Epub 2018 Jun 19.

Abstract

Inhibition of more than one pathway in a cancer cell with a single molecule could result in better therapies with less complex dosing regimens. In this work multi-component ligands have been prepared by joining together key pharmacophores of two different enzyme inhibitors in a way which increases potency against the individual pathways. Selective JAK1/2 inhibitor, ruxolitinib (3), and pan-HDAC inhibitor vorinostat (4) were linked together by a single nitrogen atom to create a new series of compounds with very potent JAK2 and HDAC6 inhibition with selectivity against HDAC1. A preferred compound, 13b, had unprecedented sub-nanomolar JAK2 potency with an IC50 of 41 pM and a sub-nanomolar IC50 against HDAC6 of 200 pM. Binding models show a good fit into both JAK2 and HDAC6.

Keywords: Designed Multiple Ligand; Histone Deacetylase; Janus kinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Histone Deacetylase 6 / antagonists & inhibitors*
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Janus Kinase 2 / antagonists & inhibitors*
  • Nitriles
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacology*
  • Pyrimidines
  • Structure-Activity Relationship
  • Vorinostat / chemistry*
  • Vorinostat / pharmacology*

Substances

  • Histone Deacetylase Inhibitors
  • Nitriles
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Vorinostat
  • ruxolitinib
  • JAK2 protein, human
  • Janus Kinase 2
  • HDAC6 protein, human
  • Histone Deacetylase 6