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European Journal of Medicinal Chemistry May 2024The continued growth of data from biological screening and medicinal chemistry provides opportunities for data-driven experimental design and decision making in... (Review)
Review
The continued growth of data from biological screening and medicinal chemistry provides opportunities for data-driven experimental design and decision making in early-phase drug discovery. Approaches adopted from data science help to integrate internal and public domain data and extract knowledge from historical in-house data. Protein kinase (PK) drug discovery is an exemplary area where large amounts of data are accumulating, providing a valuable knowledge base for discovery projects. Herein, the evolution of PK drug discovery and development of small molecular PK inhibitors (PKIs) is reviewed, highlighting milestone developments in the field and discussing exemplary studies providing a basis for increasing data orientation of PK discovery efforts.
Topics: Drug Discovery; Protein Kinase Inhibitors; Humans; Protein Kinases; Molecular Structure
PubMed: 38636127
DOI: 10.1016/j.ejmech.2024.116413 -
Frontiers in Immunology 2021Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies the donor immune... (Review)
Review
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies the donor immune system driven graft--leukemia effect. However, the therapy is mainly limited by severe acute and chronic graft--host disease (GvHD), both being life-threatening complications after allo-HCT. GvHD develops when donor T cells do not only recognize remaining tumor cells as foreign, but also the recipient's tissue, leading to a severe inflammatory disease. Typical GvHD target organs include the skin, liver and intestinal tract. Currently all approved strategies for GvHD treatment are immunosuppressive therapies, with the first-line therapy being glucocorticoids. However, therapeutic options for glucocorticoid-refractory patients are still limited. Novel therapeutic approaches, which reduce GvHD severity while preserving GvL activity, are urgently needed. Targeting kinase activity with small molecule inhibitors has shown promising results in preclinical animal models and clinical trials. Well-studied kinase targets in GvHD include Rho-associated coiled-coil-containing kinase 2 (ROCK2), spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) to control B- and T-cell activation in acute and chronic GvHD. Janus Kinase 1 (JAK1) and 2 (JAK2) are among the most intensively studied kinases in GvHD due to their importance in cytokine production and inflammatory cell activation and migration. Here, we discuss the role of kinase inhibition as novel treatment strategies for acute and chronic GvHD after allo-HCT.
Topics: Acute Disease; Animals; Chronic Disease; Graft vs Host Disease; Humans; Protein Kinase Inhibitors; Protein Kinases
PubMed: 34868001
DOI: 10.3389/fimmu.2021.760199 -
IUBMB Life Apr 2023Protein phosphorylation is a fundamental element of cell signaling. First discovered as a biochemical switch in glycogen metabolism, we now know that this...
Protein phosphorylation is a fundamental element of cell signaling. First discovered as a biochemical switch in glycogen metabolism, we now know that this posttranslational modification permeates all aspects of cellular behavior. In humans, over 540 protein kinases attach phosphate to acceptor amino acids, whereas around 160 phosphoprotein phosphatases remove phosphate to terminate signaling. Aberrant phosphorylation underlies disease, and kinase inhibitor drugs are increasingly used clinically as targeted therapies. Specificity in protein phosphorylation is achieved in part because kinases and phosphatases are spatially organized inside cells. A prototypic example is compartmentalization of the cyclic adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase A through association with A-kinase anchoring proteins. This configuration creates autonomous signaling islands where the anchored kinase is constrained in proximity to activators, effectors, and selected substates. This article primarily focuses on A kinase anchoring protein (AKAP) signaling in the heart with an emphasis on anchoring proteins that spatiotemporally coordinate excitation-contraction coupling and hypertrophic responses.
Topics: Humans; Phosphorylation; A Kinase Anchor Proteins; Cyclic AMP-Dependent Protein Kinases; Signal Transduction; Protein Kinases
PubMed: 36177749
DOI: 10.1002/iub.2677 -
International Journal of Molecular... Oct 2023Apoptosis has historically been considered the primary form of programmed cell death (PCD) and is responsible for regulating cellular processes during development,... (Review)
Review
Apoptosis has historically been considered the primary form of programmed cell death (PCD) and is responsible for regulating cellular processes during development, homeostasis, and disease. Conversely, necrosis was considered uncontrolled and unregulated. However, recent evidence has unveiled the significance of necroptosis, a regulated form of necrosis, as an important mechanism of PCD alongside apoptosis. The activation of necroptosis leads to cellular membrane disruption, inflammation, and vascularization. This process is crucial in various pathological conditions, including intervertebral disc degeneration (IVDD), neurodegeneration, inflammatory diseases, multiple cancers, and kidney injury. In recent years, extensive research efforts have shed light on the molecular regulation of the necroptotic pathway. Various stimuli trigger necroptosis, and its regulation involves the activation of specific proteins such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, and the mixed lineage kinase domain-like (MLKL) pseudokinase. Understanding the intricate mechanisms governing necroptosis holds great promise for developing novel therapeutic interventions targeting necroptosis-associated IVDD. The objective of this review is to contribute to the growing body of scientific knowledge in this area by providing a comprehensive overview of necroptosis and its association with IVDD. Ultimately, these understandings will allow the development of innovative drugs that can modulate the necroptotic pathway, offering new therapeutic avenues for individuals suffering from necroptosis.
Topics: Humans; Protein Kinases; Intervertebral Disc Degeneration; Necroptosis; Apoptosis; Necrosis; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37894970
DOI: 10.3390/ijms242015292 -
Nature Reviews. Drug Discovery Jul 2019Pseudokinases are members of the protein kinase superfamily but signal primarily through noncatalytic mechanisms. Many pseudokinases contribute to the pathologies of... (Review)
Review
Pseudokinases are members of the protein kinase superfamily but signal primarily through noncatalytic mechanisms. Many pseudokinases contribute to the pathologies of human diseases, yet they remain largely unexplored as drug targets owing to challenges associated with modulation of their biological functions. Our understanding of the structure and physiological roles of pseudokinases has improved substantially over the past decade, revealing intriguing similarities between pseudokinases and their catalytically active counterparts. Pseudokinases often adopt conformations that are analogous to those seen in catalytically active kinases and, in some cases, can also bind metal cations and/or nucleotides. Several clinically approved kinase inhibitors have been shown to influence the noncatalytic functions of active kinases, providing hope that similar properties in pseudokinases could be pharmacologically regulated. In this Review, we discuss known roles of pseudokinases in disease, their unique structural features and the progress that has been made towards developing pseudokinase-directed therapeutics.
Topics: Animals; Binding Sites; Humans; Molecular Conformation; Molecular Structure; Molecular Targeted Therapy; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Small Molecule Libraries
PubMed: 30850748
DOI: 10.1038/s41573-019-0018-3 -
Nature Communications Sep 2023Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated...
Nonalcoholic steatohepatitis (NASH) is triggered by hepatocyte death through activation of caspase 6, as a result of decreased adenosine monophosphate (AMP)-activated protein kinase-alpha (AMPKα) activity. Increased hepatocellular death promotes inflammation which drives hepatic fibrosis. We show that the nuclear-localized mitogen-activated protein kinase (MAPK) phosphatase-1 (MKP1) is upregulated in NASH patients and in NASH diet fed male mice. The focus of this work is to investigate whether and how MKP1 is involved in the development of NASH. Under NASH conditions increased oxidative stress, induces MKP1 expression leading to nuclear p38 MAPK dephosphorylation and decreases liver kinase B1 (LKB1) phosphorylation at a site required to promote LKB1 nuclear exit. Hepatic deletion of MKP1 in NASH diet fed male mice releases nuclear LKB1 into the cytoplasm to activate AMPKα and prevents hepatocellular death, inflammation and NASH. Hence, nuclear-localized MKP1-p38 MAPK-LKB1 signaling is required to suppress AMPKα which triggers hepatocyte death and the development of NASH.
Topics: Animals; Male; Mice; AMP-Activated Protein Kinases; Inflammation; Mitogen-Activated Protein Kinase 14; Non-alcoholic Fatty Liver Disease; Phosphorylation; Protein Serine-Threonine Kinases
PubMed: 37669951
DOI: 10.1038/s41467-023-41145-5 -
Cell Host & Microbe Jul 2021Toxoplasma gondii translocates effector proteins into its host cell to subvert various host pathways. T. gondii effector TgIST blocks the transcription of...
Toxoplasma gondii translocates effector proteins into its host cell to subvert various host pathways. T. gondii effector TgIST blocks the transcription of interferon-stimulated genes to reduce immune defense. Interferons upregulate numerous genes, including protein kinase R (PKR), which induce necrosome formation to activate mixed-lineage-kinase-domain-like (MLKL) pseudokinase and induce necroptosis. Whether these interferon functions are targeted by Toxoplasma is unknown. Here, we examine secreted effectors that localize to the host cell nucleus and find that the chronic bradyzoite stage secretes effector TgNSM that targets the NCoR/SMRT complex, a repressor for various transcription factors, to inhibit interferon-regulated genes involved in cell death. TgNSM acts with TgIST to block IFN-driven expression of PKR and MLKL, thus preventing host cell necroptotic death and protecting the parasite's intracellular niche. The mechanism of action of TgNSM uncovers a role of NCoR/SMRT in necroptosis, assuring survival of intracellular cysts and chronic infection.
Topics: HeLa Cells; Host-Parasite Interactions; Humans; Necroptosis; Nuclear Receptor Co-Repressor 2; Protein Kinases; Protozoan Proteins; Toxoplasma; Toxoplasmosis; eIF-2 Kinase
PubMed: 34043960
DOI: 10.1016/j.chom.2021.04.016 -
Current Opinion in Chemical Biology Apr 2023Mass spectrometry-based phosphoproteomics is currently the leading methodology for the study of global kinase signaling. The scientific community is continuously... (Review)
Review
Mass spectrometry-based phosphoproteomics is currently the leading methodology for the study of global kinase signaling. The scientific community is continuously releasing technological improvements for sensitive and fast identification of phosphopeptides, and their accurate quantification. To interpret large-scale phosphoproteomics data, numerous bioinformatic resources are available that help understanding kinase network functional role in biological systems upon perturbation. Some of these resources are databases of phosphorylation sites, protein kinases and phosphatases; others are bioinformatic algorithms to infer kinase activity, predict phosphosite functional relevance and visualize kinase signaling networks. In this review, we present the latest experimental and bioinformatic tools to profile protein kinase signaling networks and provide examples of their application in biomedicine.
Topics: Proteomics; Phosphorylation; Protein Kinases; Signal Transduction; Mass Spectrometry; Phosphoproteins
PubMed: 36657259
DOI: 10.1016/j.cbpa.2022.102260 -
Molecules (Basel, Switzerland) Jan 2021Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials.... (Review)
Review
Drug discovery using small molecule inhibitors is reaching a stalemate due to low selectivity, adverse off-target effects and inevitable failures in clinical trials. Conventional chemical screening methods may miss potent small molecules because of their use of simple but outdated kits composed of recombinant enzyme proteins. Non-canonical inhibitors targeting a hidden pocket in a protein have received considerable research attention. Kii and colleagues identified an inhibitor targeting a transient pocket in the kinase DYRK1A during its folding process and termed it FINDY. FINDY exhibits a unique inhibitory profile; that is, FINDY does not inhibit the fully folded form of DYRK1A, indicating that the FINDY-binding pocket is hidden in the folded form. This intriguing pocket opens during the folding process and then closes upon completion of folding. In this review, we discuss previously established kinase inhibitors and their inhibitory mechanisms in comparison with FINDY. We also compare the inhibitory mechanisms with the growing concept of "cryptic inhibitor-binding sites." These sites are buried on the inhibitor-unbound surface but become apparent when the inhibitor is bound. In addition, an alternative method based on cell-free protein synthesis of protein kinases may allow the discovery of small molecules that occupy these mysterious binding sites. Transitional folding intermediates would become alternative targets in drug discovery, enabling the efficient development of potent kinase inhibitors.
Topics: Binding Sites; Drug Discovery; Humans; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Recombinant Proteins; Small Molecule Libraries
PubMed: 33513739
DOI: 10.3390/molecules26030651 -
Pharmacological Research Aug 2023Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic... (Review)
Review
Owing to genetic alterations and overexpression, the dysregulation of protein kinases plays a significant role in the pathogenesis of many autoimmune and neoplastic disorders and protein kinase antagonists have become an important drug target. Although the efficacy of imatinib in the treatment of chronic myelogenous leukemia in the United States in 2001 was the main driver of protein kinase inhibitor drug discovery, this was preceded by the approval of fasudil (a ROCK antagonist) in Japan in 1995 for the treatment of cerebral vasospasm. There are 21 small molecule protein kinase inhibitors that are approved in China, Japan, Europe, and South Korea that are not approved in the United Sates and 75 FDA-approved inhibitors in the United States. Of the 21 agents, eleven target receptor protein-tyrosine kinases, eight inhibit nonreceptor protein-tyrosine kinases, and two block protein-serine/threonine kinases. All 21 drugs are orally bioavailable or topically effective. Of the non-FDA approved drugs, sixteen are prescribed for the treatment of neoplastic diseases, three are directed toward inflammatory disorders, one is used for glaucoma, and fasudil is used in the management of vasospasm. The leading targets of kinase inhibitors approved by both international regulatory agencies and by the FDA are members of the EGFR family, the VEGFR family, and the JAK family. One-third of the 21 internationally approved drugs are not compliant with Lipinski's rule of five for orally bioavailable drugs. The rule of five relies on four parameters including molecular weight, number of hydrogen bond donors and acceptors, and the Log of the partition coefficient.
Topics: United States; Humans; Protein Kinase Inhibitors; Neoplasms; Protein Serine-Threonine Kinases; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Protein Kinases; Antineoplastic Agents
PubMed: 37454916
DOI: 10.1016/j.phrs.2023.106847