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Ageing Research Reviews Mar 2023Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. Motor impairment seen in PD is associated with dopaminergic neurotoxicity... (Review)
Review
Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder in the world. Motor impairment seen in PD is associated with dopaminergic neurotoxicity in the striatum, and dopaminergic neuronal death in the substantia nigra pars compacta. Cell death has a significant effect on the development and progression of PD. Extensive research over the last few decades has unveiled new regulated cell death (RCD) mechanisms that are not dependent on apoptosis such as necroptosis, ferroptosis, and others. In this review, we will overview the mechanistic pathways of different types of RCD. Unlike accidental cell death, RCD subroutines can be regulated and the RCD-associated kinases are potential druggable targets. Hence, we will address an overview and analysis of different kinases regulating apoptosis such as receptor-interacting protein kinase 1 (RIPK-1), RIPK3, mixed lineage kinase (MLK), Ataxia telangiectasia muted (ATM), cyclin-dependent kinase (CDK), death-associated protein kinase 1 (DAPK1), Apoptosis-signaling kinase-1 (ASK-1), and Leucine-rich repeat kinase-2 (LRRK2). In addition to the role of RIPK1, RIPK3, and Mixed Lineage Kinase Domain like Pseudokinase (MLKL) in necroptosis. We also overview functions of AMP-kinase (AMPK), protein kinase C (PKC), RIPK3, and ATM in ferroptosis. We will recap the anti-apoptotic, anti-necroptotic, and anti-ferroptotic effects of different kinase inhibitors in different models of PD. Finally, we will discuss future challenges in the repositioning of kinase inhibitors in PD. In conclusion, this review kicks-start targeting RCD from a kinases perspective, opening novel therapeutic disease-modifying therapeutic avenues for PD.
Topics: Humans; Parkinson Disease; Protein Kinases; Apoptosis; Cell Death; Neurodegenerative Diseases
PubMed: 36608709
DOI: 10.1016/j.arr.2022.101841 -
Trends in Pharmacological Sciences Nov 2019Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary... (Review)
Review
Kinases are attractive anticancer targets due to their central role in the growth, survival, and therapy resistance of tumor cells. This review explores the two primary kinase classes, the eukaryotic protein kinases (ePKs) and the atypical protein kinases (aPKs), and provides a structure-centered comparison of their sequences, structures, hydrophobic spines, mutation and SNP hotspots, and inhibitor interaction patterns. Despite the limited sequence similarity between these two classes, atypical kinases commonly share the archetypical kinase fold but lack conserved eukaryotic kinase motifs and possess altered hydrophobic spines. Furthermore, atypical kinase inhibitors explore only a limited number of binding modes both inside and outside the orthosteric binding site. The distribution of genetic variations in both classes shows multiple ways they can interfere with kinase inhibitor binding. This multilayered review provides a research framework bridging the eukaryotic and atypical kinase classes.
Topics: Amino Acid Sequence; Antineoplastic Agents; Binding Sites; Humans; Models, Molecular; Neoplasms; Polymorphism, Single Nucleotide; Protein Conformation, beta-Strand; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship
PubMed: 31677919
DOI: 10.1016/j.tips.2019.09.002 -
Chemical Biology & Drug Design Dec 2022Protein kinases are key regulators of cellular signaling and play a critical role in oncogenesis. Inhibitors of protein kinases are pursued by both industry and academia... (Review)
Review
Protein kinases are key regulators of cellular signaling and play a critical role in oncogenesis. Inhibitors of protein kinases are pursued by both industry and academia as a promising target for cancer therapy. Within the protein kinases, the ATP site has produced more than 40 FDA-approved drugs. The ATP site is broadly composed of a hinge region, gatekeeper residues, DFG-loop, ribose pocket, and other hydrophobic regions. The hinge region in the ATP site can be used for designing potent inhibitors. In this review, we discuss some representative studies that will highlight the interactions of heterocyclic compounds with hinge regions of different kinases like BRAF kinase, EGRF kinase, MAP kinase, and Mps1 kinase.
Topics: Protein Kinase Inhibitors; Chemistry, Pharmaceutical; Protein Kinases; Adenosine Triphosphate
PubMed: 35112799
DOI: 10.1111/cbdd.14024 -
Drug Discovery Today Dec 2023Inflammation and cell death processes positively control the organ homeostasis of an organism. Receptor-interacting protein kinase 1 (RIPK1), a member of the RIPK... (Review)
Review
Inflammation and cell death processes positively control the organ homeostasis of an organism. Receptor-interacting protein kinase 1 (RIPK1), a member of the RIPK family, is a crucial regulator of cell death and inflammation, and control homeostasis at the cellular and tissue level. Necroptosis, a programmed form of necrosis-mediated cell death and tumor necrosis factor (TNF)-induced necrotic cell death, is mostly regulated by RIPK1 kinase activity. Thus, RIPK1 has recently emerged as an upstream kinase that controls multiple cellular pathways and participates in regulating inflammation and cell death. All the major cell types in the central nervous system (CNS) have been found to express RIPK1. Selective inhibition of RIPK1 has been shown to prevent neuronal cell death, which could ultimately lead to a significant reduction of neurodegeneration and neuroinflammation. In addition, the kinase structure of RIPK1 is highly conducive to the development of specific pharmacological small-molecule inhibitors. These factors have led to the emergence of RIPK1 as an important therapeutic target for Alzheimer's disease (AD).
Topics: Humans; Apoptosis; Alzheimer Disease; Necrosis; Protein Kinases; Inflammation; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37633326
DOI: 10.1016/j.drudis.2023.103750 -
Vascular Pharmacology Dec 2023Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in the Western world. Multiple molecular and cellular processes underpinning the... (Review)
Review
Cardiovascular disease (CVD) is the primary cause of morbidity and mortality in the Western world. Multiple molecular and cellular processes underpinning the pathogenesis of CVD are regulated by the zinc finger transcription factor and product of an immediate-early gene, early growth response-1 (Egr-1). Egr-1 regulates multiple pro-inflammatory processes that underpin the manifestation of CVD. The activity of Egr-1 itself is influenced by a range of post-translational modifications including sumoylation, ubiquitination and acetylation. Egr-1 also undergoes phosphorylation by protein kinases, such as extracellular-signal regulated kinase (ERK) which is itself phosphorylated by MEK. This article reviews recent progress on the MEK-ERK-Egr-1 cascade, notably regulation in conjunction with factors and agents such as TET2, TRIB2, MIAT, SphK1, cAMP, teneligliptin, cholinergic drugs, red wine and flavonoids, wogonin, febuxostat, docosahexaenoic acid and AT1R blockade. Such insights should provide new opportunity for therapeutic intervention in CVD.
Topics: Humans; Extracellular Signal-Regulated MAP Kinases; Cardiovascular Diseases; Transcription Factors; Phosphorylation; Mitogen-Activated Protein Kinase Kinases; Calcium-Calmodulin-Dependent Protein Kinases
PubMed: 37734428
DOI: 10.1016/j.vph.2023.107232 -
Biomolecules Jul 2022The discovery of protein kinase playing key roles in cancer formation and progression has triggered great interest and stimulated intense research on signaling pathways...
The discovery of protein kinase playing key roles in cancer formation and progression has triggered great interest and stimulated intense research on signaling pathways to develop targeted treatments, as well as to identify prognostic and predictive biomarkers [...].
Topics: Biomarkers; Humans; Neoplasms; Phosphorylation; Protein Kinases; Signal Transduction
PubMed: 36008930
DOI: 10.3390/biom12081036 -
Journal of Medicinal Chemistry May 2022
Topics: Protein Kinase Inhibitors; Protein Kinases
PubMed: 35512193
DOI: 10.1021/acs.jmedchem.2c00623 -
Mitogen-Activated Protein Kinase and Exploratory Nuclear Receptor Crosstalk in Cancer Immunotherapy.International Journal of Molecular... Sep 2023The three major mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK/SAPK) are upstream regulators of the nuclear receptor superfamily (NRSF). These... (Review)
Review
The three major mitogen-activated protein kinase (MAPK) pathways (ERK1/2, p38, and JNK/SAPK) are upstream regulators of the nuclear receptor superfamily (NRSF). These ligand-activated transcription factors are divided into subclasses comprising receptors for endocrine hormones, metabolic compounds (e.g., vitamins, diet), xenobiotics, and mediators released from host immune reactions such as tissue injury and inflammation. These internal and external cues place the NRSF at the frontline as sensors and translators of information from the environment towards the genome. For most of the former "orphan" receptors, physiological and synthetic ligands have been identified, opening intriguing opportunities for combination therapies with existing cancer medications. Hitherto, only preclinical data are available, warranting further validation in clinical trials in patients. The current review summarized the existing literature covering the expression and function of NRSF subclasses in human solid tumors and hematopoietic malignancies and their modulatory effects on innate (e.g., macrophages, dendritic cells) and adaptive (i.e., T cell subsets) immune cells, encouraging mechanistic and pharmacological studies in combination with current clinically approved therapeutics against immune checkpoint molecules (e.g., PD1).
Topics: Humans; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases; Receptors, Cytoplasmic and Nuclear; Immunotherapy; Neoplasms
PubMed: 37833991
DOI: 10.3390/ijms241914546 -
Trends in Biochemical Sciences Jan 2020Protein-protein interactions often regulate the activity of protein kinases by allosterically modulating the conformation of the ATP-binding site. Bidirectional... (Review)
Review
Protein-protein interactions often regulate the activity of protein kinases by allosterically modulating the conformation of the ATP-binding site. Bidirectional allostery implies that reverse modulation (i.e., from the ATP-binding site to the interaction and regulatory sites) must also be possible. Here, we review both the allosteric regulation of protein kinases and recent work describing how compounds binding at the ATP-binding site can promote or inhibit protein kinase interactions at regulatory sites via the reverse mechanism. Notably, the pharmaceutical industry has been developing compounds that bind to the ATP-binding site of protein kinases and potently disrupt protein-protein interactions between target protein kinases and their regulatory interacting partners. Learning to modulate allosteric processes will facilitate the development of protein-protein interaction modulators.
Topics: Adenosine Triphosphate; Allosteric Regulation; Humans; Protein Binding; Protein Kinases
PubMed: 31690482
DOI: 10.1016/j.tibs.2019.09.007 -
International Journal of Molecular... Mar 2022Mitogen-activated protein kinases (MAPKs) form tightly controlled signaling cascades that play essential roles in plant growth, development, and defense response.... (Review)
Review
Mitogen-activated protein kinases (MAPKs) form tightly controlled signaling cascades that play essential roles in plant growth, development, and defense response. However, the molecular mechanisms underlying MAPK cascades are still very elusive, largely because of our poor understanding of how they relay the signals. The MAPK cascade is composed of MAPK, MAPKK, and MAPKKK. They transfer signals through the phosphorylation of MAPKKK, MAPKK, and MAPK in turn. MAPKs are organized into a complex network for efficient transmission of specific stimuli. This review summarizes the research progress in recent years on the classification and functions of MAPK cascades under various conditions in plants, especially the research status and general methods available for identifying MAPK substrates, and provides suggestions for future research directions.
Topics: MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase Kinases; Mitogen-Activated Protein Kinases; Plant Development
PubMed: 35269886
DOI: 10.3390/ijms23052744