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Cited by 8Alzheimer's disease research and treatmentsMass Spectrometry Techniques and ApplicationsAdvanced Proteomics Techniques and Applications

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An identification of MARK inhibitors using high throughput MALDI-TOF mass spectrometry

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Hruba, Lenka, Polishchuk, Pavel, Das, Viswanath, Hajduch, Marian, Dzubak, Petr·2022·Biomedicine & Pharmacotherapy
DOI 10.1016/j.biopha.2021.112549
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Abstract

MAP/microtubule affinity-regulating kinases (MARKs) were recently identified as potential drug targets for Alzheimer's disease (AD) due to their role in pathological hyperphosphorylation of tau protein. Hyperphosphorylated tau has decreased affinity for microtubule binding, impairing their stability and associated functions. Destabilization of microtubules in neuronal cells leads to neurodegeneration, and microtubule-unbound tau forms neurofibrillary tangles, one of the primary hallmarks of AD. Many phosphorylation sites of tau protein have been identified, but phosphorylation at Ser262, which occurs in early stages of AD, plays a vital role in the pathological hyperphosphorylation of tau. It has been found that Ser262 is phosphorylated by MARK4, which is currently an intensively studied target for treating Alzheimer's disease and other neurodegenerative diseases. Our present study aimed to develop a high throughput compatible assay to directly detect MARK enzymatic activity using echoacoustic transfer and MALDI-TOF mass spectrometer. We optimized the assay for all four isoforms of MARK and validated its use for identifying potential inhibitors by the screening of 1280 compounds from the LOPAC®1280 International (Library Of Pharmacologically Active Compounds). Six MARK4 inhibitors with IC50 < 1 µM were identified. To demonstrate their therapeutic potential, active compounds were further tested for MARK4 selectivity and ability to cross the blood-brain barrier. Lastly, the molecular docking with the most active inhibitors to predict their interaction with MARK4 was performed.

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Metadata

Authors
Hruba, L., Polishchuk, P., Das, V., Hajduch, M., & Dzubak, P.
Affiliations
Institute of Molecular and Translational Medicine (CZ)
ORCID
Das, Viswanath
Venue
Biomedicine & Pharmacotherapy
Publisher
Elsevier BV
Published
2022-02
Volume
146
Pages
112549
ISSN
0753-3322 (ISSN-L)
DOI
10.1016/j.biopha.2021.112549
OpenAlex
W4200391129
Cited by
8
References
2
Citations by year
2026: 1 · 2025: 1 · 2024: 4 · 2023: 1 · 2022: 1
FWCI
0.95
Type
journal article
Language
en
Open access
Licence
Locations
  • Biomedicine & Pharmacotherapy (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Grantová Agentura České Republiky (19-08124S)
  • Univerzita Palackého v Olomouci (IGA_LF_2021_038)
  • European Regional Development Fund (CZ.02.1.01/0.0/0.0/16_019/0000868)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (CZ-OPENSCREEN – LM2018130, EATRIS-CZ – LM2018133)
  • Technologická agentura České republiky
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
  • Physical Sciences › Chemistry › Spectroscopy › Mass Spectrometry Techniques and Applications
  • Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
Keywords
MARK4, Alzheimer's disease, tau hyperphosphorylation, microtubule binding, neurofibrillary tangles, blood-brain barrier permeability, molecular docking, drug target identification
MeSH terms
Alzheimer Disease, Blood-Brain Barrier, Microtubules, Phosphorylation, tau Proteins, Protein Serine-Threonine Kinases, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Inhibitory Concentration 50, Molecular Docking Simulation

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