Discovery of type II inhibitors of TGFβ-activated kinase 1 (TAK1) and mitogen-activated protein kinase kinase kinase kinase 2 (MAP4K2)

J Med Chem. 2015 Jan 8;58(1):183-96. doi: 10.1021/jm500480k. Epub 2014 Jul 30.

Abstract

We developed a pharmacophore model for type II inhibitors that was used to guide the construction of a library of kinase inhibitors. Kinome-wide selectivity profiling of the library resulted in the identification of a series of 4-substituted 1H-pyrrolo[2,3-b]pyridines that exhibited potent inhibitory activity against two mitogen-activated protein kinases (MAPKs), TAK1 (MAP3K7) and MAP4K2, as well as pharmacologically well interrogated kinases such as p38α (MAPK14) and ABL. Further investigation of the structure-activity relationship (SAR) resulted in the identification of potent dual TAK1 and MAP4K2 inhibitors such as 1 (NG25) and 2 as well as MAP4K2 selective inhibitors such as 16 and 17. Some of these inhibitors possess good pharmacokinetic properties that will enable their use in pharmacological studies in vivo. A 2.4 Å cocrystal structure of TAK1 in complex with 1 confirms that the activation loop of TAK1 assumes the DFG-out conformation characteristic of type II inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Area Under Curve
  • Blotting, Western
  • Cell Line
  • Cell Survival / drug effects
  • Cells, Cultured
  • Drug Design
  • Drug Discovery
  • Germinal Center Kinases
  • Humans
  • MAP Kinase Kinase Kinases / antagonists & inhibitors
  • MAP Kinase Kinase Kinases / chemistry*
  • MAP Kinase Kinase Kinases / metabolism
  • Male
  • Mice
  • Models, Chemical
  • Models, Molecular
  • Molecular Structure
  • Phosphorylation / drug effects
  • Protein Binding
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / chemistry*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteome / antagonists & inhibitors
  • Proteome / chemistry
  • Proteome / metabolism
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacokinetics
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Germinal Center Kinases
  • Protein Kinase Inhibitors
  • Proteome
  • Pyridines
  • Small Molecule Libraries
  • Protein-Serine-Threonine Kinases
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7