Targeting Human Central Nervous System Protein Kinases:An Isoform Selective p38αMAPK Inhibitor That Attenuates DiseaseProgression in Alzheimer’s Disease Mouse Models

摘要

The first kinase inhibitor drug approval in 2001 initiated a remarkable decade of tyrosine kinase inhibitor drugs for oncology indications, but a void exists for serine/threonine protein kinase inhibitor drugs and central nervous system indications. Stress kinases are of special interest in neurological and neuropsychiatric disorders due to their involvement in synaptic dysfunction and complex disease susceptibility. Clinical and preclinical evidence implicates the stress related kinase p38αMAPK as a potential neurotherapeutic target, but isoform selective p38αMAPK inhibitor candidates are lacking and the mixed kinase inhibitor drugs that are promising in peripheral tissue disease indications have limitations for neurologic indications. Therefore, pursuit of the neurotherapeutic hypothesis requires kinase isoform selective inhibitors with appropriate neuropharmacology features. Synaptic dysfunction disorders offer a potential for enhanced pharmacological efficacy due to stress-induced activation of p38αMAPK in both neurons and glia, the interacting cellular components of the synapticpathophysiological axis, to be modulated. We report a novel isoformselective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), thatis efficacious in suppression of hippocampal-dependent associativeand spatial memory deficits in two distinct synaptic dysfunction mousemodels. A synthetic scheme for biocompatible product and positiveoutcomes from pharmacological screens are presented. The high-resolutioncrystallographic structure of the p38αMAPK/MW150 complex documentsactive site binding, reveals a potential low energy conformation ofthe bound inhibitor, and suggests a structural explanation for MW150’sexquisite target selectivity. As far as we are aware, MW150 is withoutprecedent as an isoform selective p38MAPK inhibitor or as a kinaseinhibitor capable of modulating in vivo stress related behavior.