2. Academic Validation
  3. Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents

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.
Pieter H Bos 1,  Emily R Lowry 2,  Jonathon Costa 2,  Sebastian Thams 2,  Alejandro Garcia-Diaz 3,  Arie Zask 1,  Hynek Wichterle 4,  Brent R Stockwell 5
Affiliations

Affiliations

  • 1 Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
  • 2 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 3 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032, USA.
  • 4 Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Neurology, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Neuroscience, Columbia University Irving Medical Center, New York, NY 10032, USA; Department of Rehabilitation and Regenerative Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Center for Motor Neuron Biology and Disease, Columbia University Irving Medical Center, New York, NY 10032, USA; Columbia Stem Cell Initiative, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: hw350@columbia.edu.
  • 5 Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Department of Chemistry, Columbia University, New York, NY 10027, USA. Electronic address: bstockwell@columbia.edu.
PMID: 31676236 DOI: 10.1016/j.chembiol.2019.10.005
Abstract

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.

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