Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents

Cell Chem Biol. 2019 Dec 19;26(12):1703-1715.e37. doi: 10.1016/j.chembiol.2019.10.005. Epub 2019 Oct 31.


Disease-causing mutations in many neurodegenerative disorders lead to proteinopathies that trigger endoplasmic reticulum (ER) stress. However, few therapeutic options exist for patients with these diseases. Using an in vitro screening platform to identify compounds that protect human motor neurons from ER stress-mediated degeneration, we discovered that compounds targeting the mitogen-activated protein kinase kinase kinase kinase (MAP4K) family are neuroprotective. The kinase inhibitor URMC-099 (compound 1) stood out as a promising lead compound for further optimization. We coupled structure-based compound design with functional activity testing in neurons subjected to ER stress to develop a series of analogs with improved MAP4K inhibition and concomitant increases in potency and efficacy. Further structural modifications were performed to enhance the pharmacokinetic profiles of the compound 1 derivatives. Prostetin/12k emerged as an exceptionally potent, metabolically stable, and blood-brain barrier-penetrant compound that is well suited for future testing in animal models of neurodegeneration.

Keywords: ALS; Alzheimer's; ER stress; MAP4Ks; Parkinson's; drug; kinase; neurodegeneration; neuroinflammation; small molecule.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Binding Sites
  • Brain / metabolism
  • Cell Differentiation
  • Cell Line
  • Endoplasmic Reticulum Stress / drug effects*
  • Half-Life
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Molecular Docking Simulation
  • Motor Neurons / cytology
  • Motor Neurons / metabolism
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacokinetics
  • Neuroprotective Agents / pharmacology*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Pyridines / chemistry
  • Pyridines / pharmacokinetics
  • Pyridines / pharmacology*
  • Pyrroles / chemistry
  • Pyrroles / pharmacokinetics
  • Pyrroles / pharmacology*
  • Signal Transduction / drug effects


  • Intracellular Signaling Peptides and Proteins
  • Neuroprotective Agents
  • Protein Kinase Inhibitors
  • Pyridines
  • Pyrroles
  • URMC-099
  • MAP4K4 protein, human
  • Protein Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases