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Microtubule affinity-regulating kinases are potential druggable targets for Alzheimer’s disease

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Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects normal functions of the brain. Currently, AD is one of the leading causes of death in developed countries and the only one of the top ten diseases without a means to prevent, cure, or significantly slow down its progression. Therefore, newer therapeutic concepts are urgently needed to improve survival and the quality of life of AD patients. Microtubule affinity-regulating kinases (MARKs) regulate tau-microtubule binding and play a crucial role in neurons. However, their role in hyperphosphorylation of tau makes them potential druggable target for AD therapy. Despite the relevance of MARKs in AD pathogenesis, only a few small molecules are known to have anti-MARK activity and not much has been done to progress these compounds into therapeutic candidates. But given the diverse role of MARKs, the specificity of novel inhibitors is imperative for their successful translation from bench to bedside. In this regard, a recent co-crystal structure of MARK4 in association with a pyrazolopyrimidine-based inhibitor offers a potential scaffold for the development of more specific MARK inhibitors. In this manuscript, we review the biological role of MARKs in health and disease, and draw attention to the largely unexplored area of MARK inhibitors for AD.

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Acknowledgements

This work was supported by Grants from the Czech Ministry of Education, Youth and Sports (Grant Numbers: LO1304, LM2011024) and Ministry of Health of the Czech Republic (Grant Number: NV15-31984A).

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  1. Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacký University, Hněvotínská 5, 77900, Olomouc, Czech Republic

    Narendran Annadurai, Khushboo Agrawal, Petr Džubák, Marián Hajdúch & Viswanath Das

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  1. Narendran Annadurai
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  2. Khushboo Agrawal
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Annadurai, N., Agrawal, K., Džubák, P. et al. Microtubule affinity-regulating kinases are potential druggable targets for Alzheimer’s disease. Cell. Mol. Life Sci. 74, 4159–4169 (2017). https://doi.org/10.1007/s00018-017-2574-1

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