title: Targeting human central nervous system protein kinases: An isoform selective p38αMAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models.
abstract: 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 synaptic pathophysiological axis, to be modulated. We report a novel isoform selective p38αMAPK inhibitor, MW01-18-150SRM (=MW150), that is efficacious in suppression of hippocampal-dependent associative and spatial memory deficits in two distinct synaptic dysfunction mouse models. A synthetic scheme for biocompatible product and positive outcomes from pharmacological screens are presented. The high-resolution crystallographic structure of the p38αMAPK/MW150 complex documents active site binding, reveals a potential low energy conformation of the bound inhibitor, and suggests a structural explanation for MW150's exquisite target selectivity. As far as we are aware, MW150 is without precedent as an isoform selective p38MAPK inhibitor or as a kinase inhibitor capable of modulating in vivo stress related behavior.
authors: †Northwestern University, Chicago, Illinois 60611, United States.
authors: Saktimayee M
authors: SM
authors: Roy
authors: †Northwestern University, Chicago, Illinois 60611, United States.
authors: Valerie L
authors: VL
authors: Grum-Tokars
authors: †Northwestern University, Chicago, Illinois 60611, United States.
authors: James P
authors: JP
authors: Schavocky
authors: ‡Columbia University, New York, New York 10032, United States.
authors: Faisal
authors: F
authors: Saeed
authors: ‡Columbia University, New York, New York 10032, United States.
authors: Agnieszka
authors: A
authors: Staniszewski
authors: ‡Columbia University, New York, New York 10032, United States.
authors: Andrew F
authors: AF
authors: Teich
authors: ‡Columbia University, New York, New York 10032, United States.
authors: Ottavio
authors: O
authors: Arancio
authors: §University of Kentucky, Lexington, Kentucky 40536, United States.
authors: Adam D
authors: AD
authors: Bachstetter
authors: §University of Kentucky, Lexington, Kentucky 40536, United States.
authors: Scott J
authors: SJ
authors: Webster
authors: §University of Kentucky, Lexington, Kentucky 40536, United States.
authors: Linda J
authors: LJ
authors: Van Eldik
authors: †Northwestern University, Chicago, Illinois 60611, United States.
authors: George
authors: G
authors: Minasov
authors: †Northwestern University, Chicago, Illinois 60611, United States.
authors: Wayne F
authors: WF
authors: Anderson
authors: †Northwestern University, Chicago, Illinois 60611, United States.
authors: Jeffrey C
authors: JC
authors: Pelletier
authors: †Northwestern University, Chicago, Illinois 60611, United States.
authors: D Martin
authors: DM
authors: Watterson
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology; D000818:Animals; D001245:Association Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy / Q000503:physiopathology; D008822:Mice, Transgenic; D008862:Microsomes, Liver / Q000187:drug effects / Q000502:physiology; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D065852:Spatial Memory / Q000187:drug effects; D013569:Synapses / Q000187:drug effects / Q000502:physiology
chemical_list: D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D048308:Mitogen-Activated Protein Kinase 14
keywords: Signal transduction; chemical synthesis; cognitive dysfunction; crystallography; pharmacology; protein kinase