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Journal of Medicinal Chemistry Jan 2023The death-associated protein kinase (DAPK) family is a member of the calcium/calmodulin-regulated serine/threonine protein kinase family, and studies have shown that its... (Review)
Review
The death-associated protein kinase (DAPK) family is a member of the calcium/calmodulin-regulated serine/threonine protein kinase family, and studies have shown that its role, as its name suggests, is mainly to regulate cell death. The DAPK family comprises five members, including DAPK1, DAPK2, DAPK3, DRAK1 and DRAK2, which show high homology in the common N-terminal kinase domain but differ in the extra-catalytic domain. Notably, previous research has suggested that the DAPK family plays an essential role in both the development and regulation of human diseases. However, only a few small-molecule inhibitors have been reported. In this Perspective, we mainly discuss the structure, biological function, and role of DAPKs in diseases and the currently discovered small-molecule inhibitors, providing valuable information for the development of the DAPK field.
Topics: Humans; Death-Associated Protein Kinases; Protein Serine-Threonine Kinases; Catalytic Domain; Calcium-Calmodulin-Dependent Protein Kinases
PubMed: 36645394
DOI: 10.1021/acs.jmedchem.2c01606 -
Pharmacological Reviews Oct 2022The number of cancer drugs is increasing as new chemical entities are developed to target molecules, often protein kinases, driving cancer progression. In 2009, Fedorov... (Review)
Review
The number of cancer drugs is increasing as new chemical entities are developed to target molecules, often protein kinases, driving cancer progression. In 2009, Fedorov et al. identified that of the protein kinases in the human kinome, most of the focus has been on a small subset. They highlighted that many poorly investigated protein kinases were cancer drivers, but there was no relationship between publications and involvement in cancer development or progression. Since 2009, there has been a doubling in the number of publications, patents, and drugs targeting the kinome. To determine whether this was an expansion in knowledge of well-studied targets-searching in the light under the lamppost-or an explosion of investigations into previously poorly investigated targets, we searched the literature for publications on each kinase, updating Federov et al.'s assessment of the druggable kinome. The proportion of papers focusing on the 50 most-studied kinases had not changed, and the makeup of those 50 had barely changed. The majority of new drugs (80%) were against the same group of 50 kinases identified as targets 10 years ago, and the proportion of studies investigating previously poorly investigated kinases (1%) was unchanged. With three exceptions [p38 mitogenactivated protein kinase (p38a), AMP-activated protein kinase catalytic -subunit 1,2, and B-Raf proto-oncogene (BRAF) serine/threonine kinase], 95% of publications addressing kinases still focused on a relatively small proportion (50%) of the human kinome independently of their involvement as cancer drivers. There is, therefore, still extensive scope for discovery of therapeutics targeting different protein kinases in cancer and still a bias toward well-characterized targets over the innovative searchlight into the unknown. SIGNIFICANCE STATEMENT: This study presents evidence that drug discovery efforts in cancer are still to some extent focused on a narrow group of well-studied kinases 10 years after the identification of multiple novel cancer targets in the human kinome. This suggests that there is still room for researchers in academia, industry, and the not-for-profit sector to develop new and diverse therapies targeting kinases for cancer.
Topics: AMP-Activated Protein Kinases; Antineoplastic Agents; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins B-raf; Serine
PubMed: 36180110
DOI: 10.1124/pharmrev.121.000410 -
Current Opinion in Chemical Biology Aug 2017Reversible protein phosphorylation regulates virtually all aspects of life in the cell. As a result, dysregulation of protein kinases, the enzymes responsible for... (Review)
Review
Reversible protein phosphorylation regulates virtually all aspects of life in the cell. As a result, dysregulation of protein kinases, the enzymes responsible for transferring phosphate groups from ATP to proteins, are often the cause or consequence of many human diseases including cancer. Almost three dozen protein kinase inhibitors (PKIs) have been approved for clinical applications since 1995, the vast majority of them for the treatment of cancer. According to the NCI, there are more than 100 types of cancer. However, FDA-approved PKIs only target 14 of them. Importantly, of the more than 500 protein kinases encoded by the human genome, only 22 are targets for currently approved PKIs, suggesting that the reservoir of PKIs still has room to grow significantly. In this short review we will discuss the most recent advances, challenges, and alternatives to currently adopted strategies in this burgeoning field.
Topics: Adenosine Triphosphate; Drug Discovery; Humans; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Kinases; Small Molecule Libraries
PubMed: 28732278
DOI: 10.1016/j.cbpa.2017.06.015 -
European Journal of Medicinal Chemistry Apr 2021Identifying a pharmacological agent that targets only one of more than 500 kinases present in humans is an important challenge. One potential solution to this problem is... (Review)
Review
Identifying a pharmacological agent that targets only one of more than 500 kinases present in humans is an important challenge. One potential solution to this problem is the development of bivalent kinase inhibitors, which consist of two connected fragments, each bind to a dissimilar binding site of the bisubstrate enzyme. The main advantage of bivalent (type V) kinase inhibitors is generating more interactions with target enzymes that can enhance the molecules' selectivity and affinity compared to single-site inhibitors. Earlier type V inhibitors were not suitable for the cellular environment and were mostly used in in vitro studies. However, recently developed bivalent compounds have high kinase affinity, high biological and chemical stability in vivo. This review summarized the hetero-bivalent kinase inhibitors described in the literature from 2014 to the present. We attempted to classify the molecules by serine/threonine and tyrosine kinase inhibitors, and then each target kinase and its hetero-bivalent inhibitor was assessed in depth. In addition, we discussed the analysis of advantages, limitations, and perspectives of bivalent kinase inhibitors compared with the monovalent kinase inhibitors.
Topics: Cyclic AMP-Dependent Protein Kinases; Extracellular Signal-Regulated MAP Kinases; Humans; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Receptor, EphA1; Small Molecule Libraries; TOR Serine-Threonine Kinases; src-Family Kinases
PubMed: 33730624
DOI: 10.1016/j.ejmech.2021.113318 -
Journal of Medicinal Chemistry Oct 2018Small molecule inhibitors targeting autoimmune and inflammatory processes have been an area of intense focus within academia and industry. Much of this work has been... (Review)
Review
Small molecule inhibitors targeting autoimmune and inflammatory processes have been an area of intense focus within academia and industry. Much of this work has been aimed at key kinases operating as central nodes in inflammatory signaling pathways. While this focus has led to over 30 FDA-approved small molecule kinase inhibitors, only one is currently approved for autoimmune and inflammatory diseases. Despite this lack of success, there remains tremendous reason for excitement. Our growing understanding of the biology involved in the inflammatory response, the factors that lead to safer small molecule kinase inhibitors, and the availability of selective tool molecules for interrogating specific nodes and pathways are all pushing the field forward. This article focuses on recent developments requiring novel approaches to create safe and effective small molecule kinase inhibitors and where further work is needed to realize the promise of small molecule kinase inhibitors for patient benefit.
Topics: Animals; Drug Discovery; Humans; Immune System Diseases; Protein Kinase Inhibitors; Protein Kinases
PubMed: 29870256
DOI: 10.1021/acs.jmedchem.8b00667 -
The Journal of Biological Chemistry 2021The mitogen-activated protein kinase (MAPK) cascade is a fundamental signaling pathway that regulates cell fate decisions in response to external stimuli. Several...
The mitogen-activated protein kinase (MAPK) cascade is a fundamental signaling pathway that regulates cell fate decisions in response to external stimuli. Several scaffold proteins bind directly to kinase components of this pathway and regulate their activation by growth factors. One of the best studied MAPK scaffolds is kinase suppressor of Ras1 (KSR1), which is induced by epidermal growth factor (EGF) to translocate to the plasma membrane where it activates extracellular signal-regulated kinase (ERK). While Ca has been shown to modulate MAPK signaling, the molecular mechanisms by which this occurs are incompletely understood. Here we tested the hypothesis that Ca alters MAPK activity at least in part via KSR1. Using several approaches, including fusion proteins, immunoprecipitation, confocal microscopy, and a cell-permeable chemical inhibitor, we investigated the functional interaction between KSR1 and calmodulin. In vitro analysis with pure proteins reveals that calmodulin binds directly to KSR1. Moreover, endogenous calmodulin and KSR1 co-immunoprecipitate from mammalian cell lysates. Importantly, Ca is required for the association between calmodulin and KSR1, both in vitro and in cells. The cell-permeable calmodulin antagonist CGS9343B significantly reduced activation of ERK by EGF in mouse embryo fibroblasts that overexpress KSR1, but not in control cells. Moreover, CGS9343B impaired the ability of EGF to induce KSR1 translocation to the plasma membrane and to stimulate formation of KSR1-ERK and KSR1-pERK (phosphorylated ERK) complexes in cells. Collectively, our data identify a previously unrecognized mechanism by which the scaffold protein KSR1 couples Ca and calmodulin signaling to the MAPK cascade.
Topics: Animals; Calmodulin; MAP Kinase Signaling System; Mice; Mitogen-Activated Protein Kinases; Protein Binding; Protein Kinases
PubMed: 33766558
DOI: 10.1016/j.jbc.2021.100577 -
Future Medicinal Chemistry Apr 2016Interest in the application of molecular dynamics (MD) simulations has increased in the field of protein kinase (PK) drug discovery. PKs belong to an important drug... (Review)
Review
Interest in the application of molecular dynamics (MD) simulations has increased in the field of protein kinase (PK) drug discovery. PKs belong to an important drug target class because they are directly involved in a number of diseases, including cancer. MD methods simulate dynamic biological and chemical events at an atomic level. This information can be combined with other in silico and experimental methods to efficiently target selected receptors. In this review, we present common and advanced methods of MD simulations and we focus on the recent applications of MD-based methodologies that provided significant insights into the elucidation of biological mechanisms involving PKs and into the discovery of novel kinase inhibitors.
Topics: Drug Design; Drug Discovery; Molecular Docking Simulation; Molecular Dynamics Simulation; Molecular Targeted Therapy; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Protein Kinases
PubMed: 27054816
DOI: 10.4155/fmc.16.9 -
Structure (London, England : 1993) Apr 2023Protein kinases of the dystonia myotonica protein kinase (DMPK) family are critical regulators of actomyosin contractility in cells. The DMPK kinase MRCK1 is required...
Protein kinases of the dystonia myotonica protein kinase (DMPK) family are critical regulators of actomyosin contractility in cells. The DMPK kinase MRCK1 is required for the activation of myosin, leading to the development of cortical tension, apical constriction, and early gastrulation. Here, we present the structure, conformation, and membrane-binding properties of Caenorhabditis elegans MRCK1. MRCK1 forms a homodimer with N-terminal kinase domains, a parallel coiled coil of 55 nm, and a C-terminal tripartite module of C1, pleckstrin homology (PH), and citron homology (CNH) domains. We report the high-resolution structure of the membrane-binding C1-PH-CNH module of MRCK1 and, using high-throughput and conventional liposome-binding assays, determine its binding to specific phospholipids. We further characterize the interaction of the C-terminal CRIB motif with Cdc42. The length of the coiled-coil domain of DMPK kinases is remarkably conserved over millions of years of evolution, suggesting that they may function as molecular rulers to position kinase activity at a fixed distance from the membrane.
Topics: Animals; Protein Serine-Threonine Kinases; Myotonic Dystrophy; Myotonin-Protein Kinase; Amino Acid Sequence; Protein Kinases; Caenorhabditis elegans
PubMed: 36854301
DOI: 10.1016/j.str.2023.02.002 -
Biochimica Et Biophysica Acta.... Oct 2023Necroptosis, a cell death modality that is defined as a necrosis-like cell death depending on the receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase... (Review)
Review
Necroptosis, a cell death modality that is defined as a necrosis-like cell death depending on the receptor-interacting protein kinase 3 (RIPK3) and mixed lineage kinase domain-like pseudokinase (MLKL), has been found to underlie the injury of various organs. Nevertheless, the molecular background of this cell loss seems to also involve, at least under certain circumstances, some novel axes, such as RIPK3-PGAM5-Drp1 (mitochondrial protein phosphatase 5-dynamin-related protein 1), RIPK3-CaMKII (Ca/calmodulin-dependent protein kinase II) and RIPK3-JNK-BNIP3 (c-Jun N-terminal kinase-BCL2 Interacting Protein 3). In addition, endoplasmic reticulum stress and oxidative stress via the higher production of reactive oxygen species produced by the mitochondrial enzymes and the enzymes of the plasma membrane have been implicated in necroptosis, thereby depicting an inter-organelle interplay in the mechanisms of this cell death. However, the role and relationship between these novel non-conventional signalling and the well-accepted canonical pathway in terms of tissue- and/or disease-specific prioritisation is completely unknown. In this review, we provide current knowledge on some necroptotic pathways being not directly associated with RIPK3-MLKL execution and report studies showing the role of respective microRNAs in the regulation of necroptotic injury in the heart and in some other tissues having a high expression of the pro-necroptotic proteins.
Topics: Humans; Necroptosis; Protein Kinases; Necrosis; Cell Death; Organelles
PubMed: 37399908
DOI: 10.1016/j.bbamcr.2023.119534 -
Expert Opinion on Therapeutic Patents 2023The mitogen-activated protein kinase (MAPK) family consist of p38 MAP kinases, c-Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinases (ERKs). They... (Review)
Review
INTRODUCTION
The mitogen-activated protein kinase (MAPK) family consist of p38 MAP kinases, c-Jun N-terminal kinases (JNKs) and extracellular signal-regulated kinases (ERKs). They are involved in a multitude of diseases, including inflammatory, autoimmune, neurodegenerative, and metabolic diseases as well as cancer. In recent years, further developments in the field of MAPK-inhibitors have been reported, including an isoform or downstream target selective inhibition of MAPKs as well as target protein degradation approaches.
AREAS COVERED
This review summarizes newly patented MAPK-inhibitors that were claimed between 2018 and early 2023. Presented are the patents as well as their corresponding publications, the storyline of development, and clinical trials involving these compounds. This article elaborates a total of 27 patents, which were identified using established search engines.
EXPERT OPINION
Although industrial research on MAPK-inhibitors has been ongoing for more than 20 years, novel clinical trials of MAPK-inhibitors as potential drug candidates are still being conducted in the period under review. Recently reported inhibitors show an excellent selectivity profile and are even achieving selectivity between closely related isoforms. This progression offers the possibility to eliminate unwanted side effects and may finally lead to the approval of the first MAPK-inhibitor.
Topics: Humans; Patents as Topic; Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases; MAP Kinase Signaling System; Phosphorylation; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors
PubMed: 37501497
DOI: 10.1080/13543776.2023.2242584