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Biochimica Et Biophysica Acta. General... Jan 2021Protein kinases play a fundamental role in the intracellular transduction because of their ability to phosphorylate plethora of proteins. Over the past three decades,... (Review)
Review
Protein kinases play a fundamental role in the intracellular transduction because of their ability to phosphorylate plethora of proteins. Over the past three decades, numerous protein kinase inhibitors have been identified and are being used clinically successfully. The biodiversity of marine organisms provides a rich source for the discovery and development of novel anticancer agents in the treatment of human malignancies and a lot of bioactive ingredients from marine organisms display anticancer effects by affecting the protein kinases-mediated pathways. In the present mini-review, anticancer compounds from marine source were reviewed and discussed in context of their targeted pathways associated with protein kinases and the progress of these compounds as anticancer agents in recent five years were emphasized. The molecular entities and their modes of actions were presented. We focused on protein kinases-mediated signaling pathways including PI3K/Akt/mTOR, p38 MAPK, and EGFR. The marine compounds targeting special pathways of protein kinases were highlighted. We have also discussed the existing challenges and prospects related to design and development of novel protein kinase inhibitors from marine sources.
Topics: Animals; Antineoplastic Agents; Aquatic Organisms; Biological Products; Drug Discovery; ErbB Receptors; Humans; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; p38 Mitogen-Activated Protein Kinases
PubMed: 33038451
DOI: 10.1016/j.bbagen.2020.129759 -
Genes Jun 2023Tremendous amount of financial resources and manpower have been invested to understand the function of numerous genes that are deregulated during the carcinogenesis... (Review)
Review
Tremendous amount of financial resources and manpower have been invested to understand the function of numerous genes that are deregulated during the carcinogenesis process, which can be targeted for anticancer therapeutic interventions. () is one of the genes that have shown potential as biomarkers for cancer treatment. It is a member of the kinase family, which also includes Death-associated protein kinase 2 (DAPK-2), Death-associated protein kinase 3 (DAPK-3), Death-associated protein kinase-related apoptosis-inducing kinase 1 (DRAK-1) and Death-associated protein kinase-related apoptosis-inducing kinase 2 (DRAK-2). is a tumour-suppressor gene that is hypermethylated in most human cancers. Additionally, DAPK-1 regulates a number of cellular processes, including apoptosis, autophagy and the cell cycle. The molecular basis by which DAPK-1 induces these cell homeostasis-related processes for cancer prevention is less understood; hence, they need to be investigated. The purpose of this review is to discuss the current understanding of the mechanisms of DAPK-1 in cell homeostasis-related processes, especially apoptosis, autophagy and the cell cycle. It also explores how the expression of DAPK-1 affects carcinogenesis. Since deregulation of DAPK-1 is implicated in the pathogenesis of cancer, altering DAPK-1 expression or activity may be a promising therapeutic strategy against cancer.
Topics: Humans; Death-Associated Protein Kinases; Calcium-Calmodulin-Dependent Protein Kinases; Apoptosis Regulatory Proteins; Apoptosis; Neoplasms; Carcinogenesis
PubMed: 37372454
DOI: 10.3390/genes14061274 -
Molecules (Basel, Switzerland) Aug 2023In drug discovery, protein kinase inhibitors (PKIs) are intensely investigated as drug candidates in different therapeutic areas. While ATP site-directed, non-covalent...
In drug discovery, protein kinase inhibitors (PKIs) are intensely investigated as drug candidates in different therapeutic areas. While ATP site-directed, non-covalent PKIs have long been a focal point in protein kinase (PK) drug discovery, in recent years, there has been increasing interest in allosteric PKIs (APKIs), which are expected to have high kinase selectivity. In addition, as compounds acting by covalent mechanisms experience a renaissance in drug discovery, there is also increasing interest in covalent PKIs (CPKIs). There are various reasons for this increasing interest such as the anticipated high potency, prolonged residence times compared to non-competitive PKIs, and other favorable pharmacokinetic properties. Due to the popularity of PKIs for therapeutic intervention, large numbers of PKIs and large volumes of activity data have accumulated in the public domain, providing a basis for large-scale computational analysis. We have systematically searched for CPKIs containing different reactive groups (warheads) and investigated their potency and promiscuity (multi-PK activity) on the basis of carefully curated activity data. For seven different warheads, sufficiently large numbers of CPKIs were available for detailed follow-up analysis. For only three warheads, the median potency of corresponding CPKIs was significantly higher than of non-covalent PKIs. However, for CKPIs with five of seven warheads, there was a significant increase in the median potency of at least 100-fold compared to PKI analogues without warheads. However, in the analysis of multi-PK activity, there was no general increase in the promiscuity of CPKIs compared to non-covalent PKIs. In addition, we have identified 29 new APKIs in X-ray structures of PK-PKI complexes. Among structurally characterized APKIs, 13 covalent APKIs in complexes with five PKs are currently available, enabling structure-based investigation of PK inhibition by covalent-allosteric mechanisms.
Topics: Protein Kinase Inhibitors; Protein Kinases; Phosphorylation; Drug Discovery
PubMed: 37570774
DOI: 10.3390/molecules28155805 -
Biochemical Society Transactions Aug 2020The protein kinase-like clan/superfamily is a large group of regulatory, signaling and biosynthetic enzymes that were historically regarded as typically eukaryotic... (Review)
Review
The protein kinase-like clan/superfamily is a large group of regulatory, signaling and biosynthetic enzymes that were historically regarded as typically eukaryotic proteins, although bacterial members have also been known for a long time. In this review, we explore the diversity of bacterial protein kinase like families, and discuss functional versatility of these enzymes, both the ones acting within the bacterial cell, and those acting within eukaryotic cells as effectors during infection. We focus on novel bacterial kinase-like families discovered in the last five years. A bioinformatics perspective is held here, hence sequence and structure comparison overview is presented, and also a comparison of genomic neighbourhoods of the families. We perform a phylum-level census of the families. Also, we discuss apparent pseudokinases that turned out to perform alternative catalytic functions by repurposing their atypical kinase-like active sites. We also highlight some 'unpopular' kinase-like families that await characterisation.
Topics: Bacteria; Catalysis; Computational Biology; Protein Conformation; Protein Kinases
PubMed: 32677675
DOI: 10.1042/BST20190712 -
Nature Chemical Biology Sep 2022The expansion of the target landscape of covalent inhibitors requires the engagement of nucleophiles beyond cysteine. Although the conserved catalytic lysine in protein...
The expansion of the target landscape of covalent inhibitors requires the engagement of nucleophiles beyond cysteine. Although the conserved catalytic lysine in protein kinases is an attractive candidate for a covalent approach, selectivity remains an obvious challenge. Moreover, few covalent inhibitors have been shown to engage the kinase catalytic lysine in animals. We hypothesized that reversible, lysine-targeted inhibitors could provide sustained kinase engagement in vivo, with selectivity driven in part by differences in residence time. By strategically linking benzaldehydes to a promiscuous kinase binding scaffold, we developed chemoproteomic probes that reversibly and covalently engage >200 protein kinases in cells and mice. Probe-kinase residence time was dramatically enhanced by a hydroxyl group ortho to the aldehyde. Remarkably, only a few kinases, including Aurora A, showed sustained, quasi-irreversible occupancy in vivo, the structural basis for which was revealed by X-ray crystallography. We anticipate broad application of salicylaldehyde-based probes to proteins that lack a druggable cysteine.
Topics: Animals; Cysteine; Lysine; Mice; Protein Binding; Protein Kinase Inhibitors; Protein Kinases
PubMed: 35590003
DOI: 10.1038/s41589-022-01019-1 -
Experimental & Molecular Medicine Jun 2021Necroptosis is a form of programmed necrosis that is mediated by various cytokines and pattern recognition receptors (PRRs). Cells dying by necroptosis show necrotic... (Review)
Review
Necroptosis is a form of programmed necrosis that is mediated by various cytokines and pattern recognition receptors (PRRs). Cells dying by necroptosis show necrotic phenotypes, including swelling and membrane rupture, and release damage-associated molecular patterns (DAMPs), inflammatory cytokines, and chemokines, thereby mediating extreme inflammatory responses. Studies on gene knockout or necroptosis-specific inhibitor treatment in animal models have provided extensive evidence regarding the important roles of necroptosis in inflammatory diseases. The necroptosis signaling pathway is primarily modulated by activation of receptor-interacting protein kinase 3 (RIPK3), which phosphorylates mixed-lineage kinase domain-like protein (MLKL), mediating MLKL oligomerization. In the necroptosis process, these proteins are fine-tuned by posttranslational regulation via phosphorylation, ubiquitination, glycosylation, and protein-protein interactions. Herein, we review recent findings on the molecular regulatory mechanisms of necroptosis.
Topics: Animals; Apoptosis; Necroptosis; Necrosis; Phosphorylation; Protein Kinases
PubMed: 34075202
DOI: 10.1038/s12276-021-00634-7 -
Genesis (New York, N.Y. : 2000) Mar 2022Protein kinases (PKs) and protein phosphatases (PPs) regulate the phosphorylation of proteins that are involved in a variety of biological processes. To study such...
Protein kinases (PKs) and protein phosphatases (PPs) regulate the phosphorylation of proteins that are involved in a variety of biological processes. To study such biological processes systematically, it is important to know the whole repertoire of PKs and PPs encoded in a genome. In the present study, we surveyed the genome of an ascidian (Ciona robusta or Ciona intestinalis type A) to comprehensively identify the genes that encoded PKs and PPs. Because ascidians belong to the sister group of vertebrates, a comparison of the whole repertoire of PKs and PPs of ascidians with those of vertebrates may help to delineate the complements of these proteins that were present in the last common ancestor of these two groups of animals. Our results show that the repertory of PPs was much more expanded in vertebrates than the repertory of PKs. We also showed that approximately 75% of PKs and PPs were expressed during development from eggs to larvae. Thus, the present study provides catalogs for PKs and PPs encoded in the ascidian genome. These catalogs will be useful for systematic studies of biological processes that involve phosphorylation and for evolutionary studies of the origin of vertebrates.
Topics: Animals; Ciona intestinalis; Genome; Phosphoprotein Phosphatases; Phylogeny; Protein Kinases; Vertebrates
PubMed: 35261143
DOI: 10.1002/dvg.23471 -
World Journal of Gastroenterology Aug 2021Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new... (Review)
Review
Pancreatic cancer is a dismal disease with high incidence and poor survival rates. With the aim to improve overall survival of pancreatic cancer patients, new therapeutic approaches are urgently needed. Protein kinases are key regulatory players in basically all stages of development, maintaining physiologic functions but also being involved in pathogenic processes. c-Jun N-terminal kinases (JNK) and p38 kinases, representatives of the mitogen-activated protein kinases, as well as the casein kinase 1 (CK1) family of protein kinases are important mediators of adequate response to cellular stress following inflammatory and metabolic stressors, DNA damage, and others. In their physiologic roles, they are responsible for the regulation of cell cycle progression, cell proliferation and differentiation, and apoptosis. Dysregulation of the underlying pathways consequently has been identified in various cancer types, including pancreatic cancer. Pharmacological targeting of those pathways has been the field of interest for several years. While success in earlier studies was limited due to lacking specificity and off-target effects, more recent improvements in small molecule inhibitor design against stress-activated protein kinases and their use in combination therapies have shown promising results. Consequently, targeting of JNK, p38, and CK1 protein kinase family members may actually be of particular interest in the field of precision medicine in patients with highly deregulated kinase pathways related to these kinases. However, further studies are warranted, especially involving investigation and clinical trials, in order to advance inhibition of stress-activated kinases to the field of translational medicine.
Topics: Apoptosis; Humans; JNK Mitogen-Activated Protein Kinases; Mitogen-Activated Protein Kinases; Pancreatic Neoplasms; p38 Mitogen-Activated Protein Kinases
PubMed: 34497429
DOI: 10.3748/wjg.v27.i30.4963 -
Autophagy Feb 2022The removal of mitochondria in a programmed or stress-induced manner is essential for maintaining cellular homeostasis. To date, much research has focused upon...
The removal of mitochondria in a programmed or stress-induced manner is essential for maintaining cellular homeostasis. To date, much research has focused upon stress-induced mitophagy that is largely regulated by the E3 ligase PRKN, with limited insight into the mechanisms regulating basal "housekeeping" mitophagy levels in different model organisms. Using iron chelation as an inducer of PRKN-independent mitophagy, we recently screened an siRNA library of lipid-binding proteins and determined that two kinases, GAK and PRKCD, act as positive regulators of PRKN-independent mitophagy. We demonstrate that PRKCD is localized to mitochondria and regulates recruitment of ULK1-ATG13 upon induction of mitophagy. GAK activity, by contrast, modifies the mitochondrial network and lysosomal morphology that compromise efficient transport of mitochondria for degradation. Impairment of either kinase blocks basal mitophagy, demonstrating the biological relevance of our findings. CCCP: carbonyl cyanide-m-chlorophenyl hydrazone; DFP: deferiprone; GAK: cyclin G associated kinase; HIF1A: hypoxia inducible factor 1 subunit alpha; PRKC/PKC: protein kinase C; PRKCD: protein kinase C delta; PRKN: parkin RBR E3 ubiquitin protein ligase.
Topics: Autophagy; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Mitophagy; Protein Kinase C-delta; Protein Kinases; Ubiquitin-Protein Ligases
PubMed: 35001811
DOI: 10.1080/15548627.2021.2015154 -
Drug Research Apr 2023Protein kinases belong to the phosphor-transferases superfamily of enzymes, which "activate" enzymes via phosphorylation. The kinome of an organism is the total set of... (Review)
Review
Protein kinases belong to the phosphor-transferases superfamily of enzymes, which "activate" enzymes via phosphorylation. The kinome of an organism is the total set of genes in the genome, which encode for all the protein kinases. Certain mutations in the kinome have been linked to dysregulation of protein kinases, which in turn can lead to several diseases and disorders including cancer. In this review, we have briefly discussed the role of protein kinases in various biochemical processes by categorizing cancer associated phenotypes and giving their protein kinase examples. Various techniques have also been discussed, which are being used to analyze the structure of protein kinases, and associate their roles in the oncogenesis. We have also discussed protein kinase inhibitors and United States Federal Drug Administration (USFDA) approved drugs, which target protein kinases and can serve as a counter to protein kinase dysregulation and mitigate the effects of oncogenesis. Overall, this review briefs about the importance of protein kinases, their roles in oncogenesis on dysregulation and how their inhibition via various drugs can be used to mitigate their effects.
Topics: Humans; Protein Kinases; Protein Kinase Inhibitors; Neoplasms; Carcinogenesis
PubMed: 36822216
DOI: 10.1055/a-1989-1856