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14 pages, 1655 KiB

Open AccessArticle

A Computational Workflow for the Identification of Novel Fragments Acting as Inhibitors of the Activity of Protein Kinase CK1δ

by Giovanni Bolcato, Eleonora Cescon, Matteo Pavan, Maicol Bissaro, Davide Bassani, Stephanie Federico, Giampiero Spalluto, Mattia Sturlese and Stefano Moro

Int. J. Mol. Sci. 2021, 22(18), 9741; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189741 - 09 Sep 2021

Cited by 15 | Viewed by 2407

Abstract

Fragment-Based Drug Discovery (FBDD) has become, in recent years, a consolidated approach in the drug discovery process, leading to several drug candidates under investigation in clinical trials and some approved drugs. Among these successful applications of the FBDD approach, kinases represent a class [...] Read more.

Fragment-Based Drug Discovery (FBDD) has become, in recent years, a consolidated approach in the drug discovery process, leading to several drug candidates under investigation in clinical trials and some approved drugs. Among these successful applications of the FBDD approach, kinases represent a class of targets where this strategy has demonstrated its real potential with the approved kinase inhibitor Vemurafenib. In the Kinase family, protein kinase CK1 isoform δ (CK1δ) has become a promising target in the treatment of different neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the present work, we set up and applied a computational workflow for the identification of putative fragment binders in large virtual databases. To validate the method, the selected compounds were tested in vitro to assess the CK1δ inhibition. Full article

(This article belongs to the Special Issue Protein Kinases and Their Inhibitors in CNS Diseases)

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14 pages, 2347 KiB

Open AccessArticle

Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis

by Loreto Martínez-González, Claudia Gonzalo-Consuegra, Marta Gómez-Almería, Gracia Porras, Eva de Lago, Ángeles Martín-Requero and Ana Martínez

Int. J. Mol. Sci. 2021, 22(16), 8975; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168975 - 20 Aug 2021

Cited by 21 | Viewed by 3458

Abstract

Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3β is one of the protein kinases involved in [...] Read more.

Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3β is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3β inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3β activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43^A315T mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year. Full article

(This article belongs to the Special Issue Protein Kinases and Their Inhibitors in CNS Diseases)

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27 pages, 6799 KiB

Open AccessArticle

Revisiting the Proposition of Binding Pockets and Bioactive Poses for GSK-3β Allosteric Modulators Addressed to Neurodegenerative Diseases

by Guilherme M. Silva, Rosivaldo S. Borges, Kelton L. B. Santos, Leonardo B. Federico, Isaque A. G. Francischini, Suzane Q. Gomes, Mariana P. Barcelos, Rai C. Silva, Cleydson B. R. Santos and Carlos H. T. P. Silva

Int. J. Mol. Sci. 2021, 22(15), 8252; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158252 - 31 Jul 2021

Cited by 9 | Viewed by 3705

Abstract

Glycogen synthase kinase-3 beta (GSK-3β) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out [...] Read more.

Glycogen synthase kinase-3 beta (GSK-3β) is an enzyme pertinently linked to neurodegenerative diseases since it is associated with the regulation of key neuropathological features in the central nervous system. Among the different kinds of inhibitors of this kinase, the allosteric ones stand out due to their selective and subtle modulation, lowering the chance of producing side effects. The mechanism of GSK-3β allosteric modulators may be considered still vague in terms of elucidating a well-defined binding pocket and a bioactive pose for them. In this context, we propose to reinvestigate and reinforce such knowledge by the application of an extensive set of in silico methodologies, such as cavity detection, ligand 3D shape analysis and docking (with robust validation of corresponding protocols), and molecular dynamics. The results here obtained were consensually consistent in furnishing new structural data, in particular by providing a solid bioactive pose of one of the most representative GSK-3β allosteric modulators. We further applied this to the prospect for new compounds by ligand-based virtual screening and analyzed the potential of the two obtained virtual hits by quantum chemical calculations. All potential hits achieved will be subsequently tested by in vitro assays in order to validate our approaches as well as to unveil novel chemical entities as GSK-3β allosteric modulators. Full article

(This article belongs to the Special Issue Protein Kinases and Their Inhibitors in CNS Diseases)

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18 pages, 4719 KiB

Open AccessArticle

CK1δ-Derived Peptides as Novel Tools Inhibiting the Interactions between CK1δ and APP695 to Modulate the Pathogenic Metabolism of APP

by Aileen Roth, Fabian Gärtner, Katja Mayer, Julian Beyrle, Irina König, Uwe Knippschild and Joachim Bischof

Int. J. Mol. Sci. 2021, 22(12), 6423; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22126423 - 15 Jun 2021

Cited by 2 | Viewed by 2178

Abstract

Alzheimer’s disease (AD) is the major cause of dementia, and affected individuals suffer from severe cognitive, mental, and functional impairment. Histologically, AD brains are basically characterized by the presence of amyloid plaques and neurofibrillary tangles. Previous reports demonstrated that protein kinase CK1δ influences [...] Read more.

Alzheimer’s disease (AD) is the major cause of dementia, and affected individuals suffer from severe cognitive, mental, and functional impairment. Histologically, AD brains are basically characterized by the presence of amyloid plaques and neurofibrillary tangles. Previous reports demonstrated that protein kinase CK1δ influences the metabolism of amyloid precursor protein (APP) by inducing the generation of amyloid-β (Aβ), finally contributing to the formation of amyloid plaques and neuronal cell death. We therefore considered CK1δ as a promising therapeutic target and suggested an innovative strategy for the treatment of AD based on peptide therapeutics specifically modulating the interaction between CK1δ and APP. Initially, CK1δ-derived peptides manipulating the interactions between CK1δ and APP695 were identified by interaction and phosphorylation analysis in vitro. Selected peptides subsequently proved their potential to penetrate cells without inducing cytotoxic effects. Finally, for at least two of the tested CK1δ-derived peptides, a reduction in Aβ levels and amyloid plaque formation could be successfully demonstrated in a complex cell culture model for AD. Consequently, the presented results provide new insights into the interactions of CK1δ and APP695 while also serving as a promising starting point for further development of novel and highly innovative pharmacological tools for the treatment of AD. Full article

(This article belongs to the Special Issue Protein Kinases and Their Inhibitors in CNS Diseases)

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18 pages, 3120 KiB

Open AccessArticle

Protein Kinase C Activation Drives a Differentiation Program in an Oligodendroglial Precursor Model through the Modulation of Specific Biological Networks

by Marina Damato, Tristan Cardon, Maxence Wisztorski, Isabelle Fournier, Damiana Pieragostino, Ilaria Cicalini, Michel Salzet, Daniele Vergara and Michele Maffia

Int. J. Mol. Sci. 2021, 22(10), 5245; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22105245 - 15 May 2021

Cited by 6 | Viewed by 2653

Abstract

Protein kinase C (PKC) activation induces cellular reprogramming and differentiation in various cell models. Although many effectors of PKC physiological actions have been elucidated, the molecular mechanisms regulating oligodendrocyte differentiation after PKC activation are still unclear. Here, we applied a liquid chromatography–mass spectrometry [...] Read more.

Protein kinase C (PKC) activation induces cellular reprogramming and differentiation in various cell models. Although many effectors of PKC physiological actions have been elucidated, the molecular mechanisms regulating oligodendrocyte differentiation after PKC activation are still unclear. Here, we applied a liquid chromatography–mass spectrometry (LC–MS/MS) approach to provide a comprehensive analysis of the proteome expression changes in the MO3.13 oligodendroglial cell line after PKC activation. Our findings suggest that multiple networks that communicate and coordinate with each other may finally determine the fate of MO3.13 cells, thus identifying a modular and functional biological structure. In this work, we provide a detailed description of these networks and their participating components and interactions. Such assembly allows perturbing each module, thus describing its physiological significance in the differentiation program. We applied this approach by targeting the Rho-associated protein kinase (ROCK) in PKC-activated cells. Overall, our findings provide a resource for elucidating the PKC-mediated network modules that contribute to a more robust knowledge of the molecular dynamics leading to this cell fate transition. Full article

(This article belongs to the Special Issue Protein Kinases and Their Inhibitors in CNS Diseases)

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18 pages, 6161 KiB

Open AccessArticle

Neuroprotective Effect of Kinase Inhibition in Ischemic Factor Modeling In Vitro

by Elena V. Mitroshina, Maria M. Loginova, Maria O. Savyuk, Mikhail I. Krivonosov, Tatiana A. Mishchenko, Viktor S. Tarabykin, Mikhail V. Ivanchenko and Maria V. Vedunova

Int. J. Mol. Sci. 2021, 22(4), 1885; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041885 - 14 Feb 2021

Cited by 8 | Viewed by 1754

Abstract

The contribution of many neuronal kinases to the adaptation of nerve cells to ischemic damage and their effect on functional neural network activity has not yet been studied. The aim of this work is to study the role of the four kinases belonging [...] Read more.

The contribution of many neuronal kinases to the adaptation of nerve cells to ischemic damage and their effect on functional neural network activity has not yet been studied. The aim of this work is to study the role of the four kinases belonging to different metabolic cascades (SRC, Ikkb, eEF2K, and FLT4) in the adaptive potential of the neuron-glial network for modeling the key factors of ischemic damage. We carried out a comprehensive study on the effects of kinases blockade on the viability and network functional calcium activity of nerve cells under ischemic factor modeling in vitro. Ischemic factor modelling was performed on day 14 of culturing primary hippocampal cells obtained from mouse embryos (E18). The most significant neuroprotective effect was shown in the blockade of FLT4 kinase in the simulation of hypoxia. The studies performed revealed the role of FLT4 in the development of functional dysfunction in cerebrovascular accidents and created new opportunities for the study of this enzyme and its blockers in the formation of new therapeutic strategies. Full article

(This article belongs to the Special Issue Protein Kinases and Their Inhibitors in CNS Diseases)

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Review

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37 pages, 10058 KiB

Open AccessReview

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

by Stefania Demuro, Rita M. C. Di Martino, Jose A. Ortega and Andrea Cavalli

Int. J. Mol. Sci. 2021, 22(16), 9098; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22169098 - 23 Aug 2021

Cited by 40 | Viewed by 4895

Abstract

Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the [...] Read more.

Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3β, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3β, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood–brain barrier (BBB) permeability and drug-like properties. Full article

(This article belongs to the Special Issue Protein Kinases and Their Inhibitors in CNS Diseases)

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25 pages, 2629 KiB

Open AccessReview

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

by Mattias F. Lindberg and Laurent Meijer

Int. J. Mol. Sci. 2021, 22(11), 6047; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116047 - 03 Jun 2021

Cited by 52 | Viewed by 7801

Abstract

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, [...] Read more.

Dual-specificity tyrosine phosphorylation-regulated kinases (DYRK1A, 1B, 2-4) and cdc2-like kinases (CLK1-4) belong to the CMGC group of serine/threonine kinases. These protein kinases are involved in multiple cellular functions, including intracellular signaling, mRNA splicing, chromatin transcription, DNA damage repair, cell survival, cell cycle control, differentiation, homocysteine/methionine/folate regulation, body temperature regulation, endocytosis, neuronal development, synaptic plasticity, etc. Abnormal expression and/or activity of some of these kinases, DYRK1A in particular, is seen in many human nervous system diseases, such as cognitive deficits associated with Down syndrome, Alzheimer’s disease and related diseases, tauopathies, dementia, Pick’s disease, Parkinson’s disease and other neurodegenerative diseases, Phelan-McDermid syndrome, autism, and CDKL5 deficiency disorder. DYRKs and CLKs are also involved in diabetes, abnormal folate/methionine metabolism, osteoarthritis, several solid cancers (glioblastoma, breast, and pancreatic cancers) and leukemias (acute lymphoblastic leukemia, acute megakaryoblastic leukemia), viral infections (influenza, HIV-1, HCMV, HCV, CMV, HPV), as well as infections caused by unicellular parasites (Leishmania, Trypanosoma, Plasmodium). This variety of pathological implications calls for (1) a better understanding of the regulations and substrates of DYRKs and CLKs and (2) the development of potent and selective inhibitors of these kinases and their evaluation as therapeutic drugs. This article briefly reviews the current knowledge about DYRK/CLK kinases and their implications in human disease. Full article

(This article belongs to the Special Issue Protein Kinases and Their Inhibitors in CNS Diseases)

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31 pages, 7528 KiB

Open AccessReview

c-Jun N-Terminal Kinase Inhibitors as Potential Leads for New Therapeutics for Alzheimer’s Diseases

by Stephanie Cristine Hepp Rehfeldt, Fernanda Majolo, Márcia Inês Goettert and Stefan Laufer

Int. J. Mol. Sci. 2020, 21(24), 9677; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21249677 - 18 Dec 2020

Cited by 25 | Viewed by 6732

Abstract

Alzheimer’s Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways [...] Read more.

Alzheimer’s Disease (AD) is becoming more prevalent as the population lives longer. For individuals over 60 years of age, the prevalence of AD is estimated at 40.19% across the world. Regarding the cognitive decline caused by the disease, mitogen-activated protein kinases (MAPK) pathways such as the c-Jun N-terminal kinase (JNK) pathway are involved in the progressive loss of neurons and synapses, brain atrophy, and augmentation of the brain ventricles, being activated by synaptic dysfunction, oxidative stress, and excitotoxicity. Nowadays, AD symptoms are manageable, but the disease itself remains incurable, thus the inhibition of JNK3 has been explored as a possible therapeutic target, considering that JNK is best known for its involvement in propagating pro-apoptotic signals. This review aims to present biological aspects of JNK, focusing on JNK3 and how it relates to AD. It was also explored the recent development of inhibitors that could be used in AD treatment since several drugs/compounds in phase III clinical trials failed. General aspects of the MAPK family, therapeutic targets, and experimental treatment in models are described and discussed throughout this review. Full article

(This article belongs to the Special Issue Protein Kinases and Their Inhibitors in CNS Diseases)

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