1. Development of MAP4 Kinase Inhibitors as Motor Neuron-Protecting Agents.
- Author
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Bos, Pieter H., Lowry, Emily R., Costa, Jonathon, Thams, Sebastian, Garcia-Diaz, Alejandro, Zask, Arie, Wichterle, Hynek, and Stockwell, Brent R.
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ENDOPLASMIC reticulum , *KINASE inhibitors , *MITOGEN-activated protein kinases , *MOTOR neurons , *NEURODEGENERATION , *LEAD compounds - 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. • MAP4K inhibitors protect motor neurons from ER stress-induced apoptosis • We synthesized URMC-099 analogs to optimize selectivity and pharmacokinetics • Prostetin/12k is an analog with enhanced MAP4K inhibition and neuroprotection • Prostetin/12k shows improved stability, CNS penetrance, and oral bioavailability Using an in vitro screening platform to identify compounds that protect neurons from ER stress, a common feature of many neurodegenerative disorders, Bos et al. identified MAP4Ks as important shared targets of neuroprotective compounds. They then developed a series of potent, stable, and brain-penetrant MAP4K inhibitors, including Prostetin/12k. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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