Volume 8 Supplement 1

Molecular Neurodegeneration: Basic biology and disease pathways

Open Access

Identification of potent inhibitors of microtubule affinity regulating kinase for inhibition of tau hyperphosphorylation

  • Alison Levy1,
  • Michelle Newman1,
  • Janet Brownlees1,
  • Denise Harding1,
  • Joanne Osborne1,
  • Stephen Lewis1,
  • Kevin Gillen1,
  • Gareth Hall2,
  • Chido Mpamhanga1,
  • Andy Merritt1,
  • Debra Taylor1 and
  • Ed Mclver1
Molecular Neurodegeneration20138(Suppl 1):P28

https://doi.org/10.1186/1750-1326-8-S1-P28

Published: 13 September 2013

The four MARK (microtubule affinity regulating kinase) kinases (MARKs 1-4) are an evolutionary conserved group of proteins, which belong to the AMPK-related protein kinase family and are involved in the regulation of cell polarity. MARKs are highly expressed in brain and were first identified through their ability to phosphorylate and regulate the dissociation of microtubule-associated proteins (MAPs) from microtubules[1]. In particular, MARK phosphorylation of the MAP tau at KXGS motifs within the microtubule-binding domain was shown to dissociate tau from microtubules leading to de-stabilisation of the microtubule network. The MARK-mediated phosphorylation of tau has also been linked to the formation of neurofibrillary tangles (NFTs) observed in Alzheimer’s Disease (AD) and other neurodegenerative diseases collectively referred to as tauopathies[2, 3]. Based on available evidence it is proposed that inhibitors of MARK could prevent the formation of hyperphosphorylated tau protein and thus be useful for the treatment of Alzheimer’s and other neurodegenerative diseases. We identified a potent chemical series of MARK inhibitors and conducted a medicinal chemistry lead optimisation program to explore SAR and improve the affinity, kinase selectivity and ADME profiles of our lead compounds. This work was aided by a combination of first in silico modelling followed by X-ray crystallography. We also developed and used a high content imaging assay to monitor tau phosphorylation at the Ser262 MARK epitope in primary rat neurons, to demonstrate the effect of MARK inhibitors in a physiologically relevant cellular environment. The aim was to identify a potent and selective ATP-competitive MARK inhibitor that could be used for ‘proof of concept’ studies in transgenic mice expressing human tau and potentially as a starting point for a drug development program.

Authors’ Affiliations

(1)
Centre for Therapeutics Discovery, MRC Technology
(2)
Department of Biochemistry, University of Leicester

References

  1. Drewes , et al: MARK, a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption. Cell. 1997, 89: 297-308. 10.1016/S0092-8674(00)80208-1.View ArticlePubMedGoogle Scholar
  2. Goedert M, Spillantini MG: A century of Alzheimers Disease. Science. 2006, 314: 777-781. 10.1126/science.1132814.View ArticlePubMedGoogle Scholar
  3. Drewes G: MARKing tau for tangles and toxicity. Trends Biochem Sci. 2004, 29: 548-555. 10.1016/j.tibs.2004.08.001.View ArticlePubMedGoogle Scholar

Copyright

© Levy et al; licensee BioMed Central Ltd. 2013

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Advertisement