4R3C

Crystal structure of p38 alpha MAP kinase in complex with a novel isoform selective drug candidate

Summary for 4R3C

• Entry DOI: 10.2210/pdb4r3c/pdb
• Related: 4EWQ 4F9W 4F9Y
• Descriptor: Mitogen-activated protein kinase 14, 4-[3-(4-FLUOROPHENYL)-1H-PYRAZOL-4-YL]PYRIDINE, 6-(4-methylpiperazin-1-yl)-3-(naphthalen-2-yl)-4-(pyridin-4-yl)pyridazine, ... (5 entities in total)
• Functional Keywords: serine/threonine-protein kinase, protein kinase domain, transferase, atp binding, phosphorylation, cytosol, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : Q16539
• Total number of polymer chains: 1
• Total formula weight: 45069.67

Authors

Grum-Tokars, V.L.,Minasov, G.,Roy, S.M.,Anderson, W.F.,Watterson, D.M. (deposition date: 2014-08-14, release date: 2015-02-25, Last modification date: 2017-11-22)

Primary citation

Roy, S.M.,Grum-Tokars, V.L.,Schavocky, J.P.,Saeed, F.,Staniszewski, A.,Teich, A.F.,Arancio, O.,Bachstetter, A.D.,Webster, S.J.,Van Eldik, L.J.,Minasov, G.,Anderson, W.F.,Pelletier, J.C.,Watterson, D.M.
Targeting human central nervous system protein kinases: An isoform selective p38 alpha MAPK inhibitor that attenuates disease progression in Alzheimer's disease mouse models.
ACS Chem Neurosci, 6:666-680, 2015

PubMed 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.

PubMed: 25676389
DOI: 10.1021/acschemneuro.5b00002

Experimental method

X-RAY DIFFRACTION (2.06 Å)