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Trends in Biochemical Sciences Apr 2018Protein kinases regulate every aspect of cellular activity, whereas metabolic enzymes are responsible for energy production and catabolic and anabolic processes.... (Review)
Review
Protein kinases regulate every aspect of cellular activity, whereas metabolic enzymes are responsible for energy production and catabolic and anabolic processes. Emerging evidence demonstrates that some metabolic enzymes, such as pyruvate kinase M2 (PKM2), phosphoglycerate kinase 1 (PGK1), ketohexokinase (KHK) isoform A (KHK-A), hexokinase (HK), and nucleoside diphosphate kinase 1 and 2 (NME1/2), that phosphorylate soluble metabolites can also function as protein kinases and phosphorylate a variety of protein substrates to regulate the Warburg effect, gene expression, cell cycle progression and proliferation, apoptosis, autophagy, exosome secretion, T cell activation, iron transport, ion channel opening, and many other fundamental cellular functions. The elevated protein kinase functions of these moonlighting metabolic enzymes in tumor development make them promising therapeutic targets for cancer.
Topics: Animals; Humans; Neoplasms; Protein Kinases
PubMed: 29463470
DOI: 10.1016/j.tibs.2018.01.006 -
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 -
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 -
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 -
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 -
Trends in Endocrinology and Metabolism:... Dec 2018The discovery of liver kinase B1 (LKB1) as an upstream kinase for AMP-activated protein kinase (AMPK) led to the identification of several related kinases that also rely... (Review)
Review
The discovery of liver kinase B1 (LKB1) as an upstream kinase for AMP-activated protein kinase (AMPK) led to the identification of several related kinases that also rely on LKB1 for their catalytic activity. Among these, the salt-inducible kinases (SIKs) have emerged as key regulators of metabolism. Unlike AMPK, SIKs do not respond to nucleotides, but their function is regulated by extracellular signals, such as hormones, through complex LKB1-independent mechanisms. While AMPK acts on multiple targets, including metabolic enzymes, to maintain cellular ATP levels, SIKs primarily regulate gene expression, by acting on transcriptional regulators, such as the cAMP response element-binding protein-regulated transcription coactivators and class IIa histone deacetylases. This review describes the development of research on SIKs, from their discovery to the most recent findings on metabolic regulation.
Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Energy Metabolism; Gluconeogenesis; Humans; Protein Serine-Threonine Kinases
PubMed: 30385008
DOI: 10.1016/j.tem.2018.09.007 -
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 -
International Journal of Molecular... Oct 2018Activated by AMP-dependent and -independent mechanisms, AMP-activated protein kinase (AMPK) plays a central role in the regulation of cellular bioenergetics and cellular... (Review)
Review
Activated by AMP-dependent and -independent mechanisms, AMP-activated protein kinase (AMPK) plays a central role in the regulation of cellular bioenergetics and cellular survival. AMPK regulates a diverse set of signaling networks that converge to epigenetically mediate transcriptional events. Reversible histone and DNA modifications, such as acetylation and methylation, result in structural chromatin alterations that influence transcriptional machinery access to genomic regulatory elements. The orchestration of these epigenetic events differentiates physiological from pathophysiological phenotypes. AMPK phosphorylation of histones, DNA methyltransferases and histone post-translational modifiers establish AMPK as a key player in epigenetic regulation. This review focuses on the role of AMPK as a mediator of cellular survival through its regulation of chromatin remodeling and the implications this has for health and disease.
Topics: AMP-Activated Protein Kinase Kinases; Animals; Chromatin Assembly and Disassembly; DNA Methylation; Epigenesis, Genetic; Histone Code; Humans; Protein Kinases
PubMed: 30347687
DOI: 10.3390/ijms19103238 -
Experimental & Molecular Medicine Apr 2022Accumulating evidence indicates that mitotic protein kinases are involved in metastatic migration as well as tumorigenesis. Protein kinases and cytoskeletal proteins... (Review)
Review
Accumulating evidence indicates that mitotic protein kinases are involved in metastatic migration as well as tumorigenesis. Protein kinases and cytoskeletal proteins play a role in the efficient release of metastatic cells from a tumor mass in the tumor microenvironment, in addition to playing roles in mitosis. Mitotic protein kinases, including Polo-like kinase 1 (PLK1) and Aurora kinases, have been shown to be involved in metastasis in addition to cell proliferation and tumorigenesis, depending on the phosphorylation status and cellular context. Although the genetic programs underlying mitosis and metastasis are different, the same protein kinases and cytoskeletal proteins can participate in both mitosis and cell migration/invasion, resulting in migratory tumors. Cytoskeletal remodeling supports several cellular events, including cell division, movement, and migration. Thus, understanding the contributions of cytoskeletal proteins to the processes of cell division and metastatic motility is crucial for developing efficient therapeutic tools to treat cancer metastases. Here, we identify mitotic kinases that function in cancer metastasis as well as tumorigenesis. Several mitotic kinases, namely, PLK1, Aurora kinases, Rho-associated protein kinase 1, and integrin-linked kinase, are considered in this review, as an understanding of the shared machineries between mitosis and metastasis could be helpful for developing new strategies to treat cancer.
Topics: Aurora Kinases; Carcinogenesis; Cell Cycle Proteins; Cytoskeletal Proteins; HeLa Cells; Humans; Mitosis; Neoplasms; Phosphorylation; Protein Kinases; Tumor Microenvironment
PubMed: 35379935
DOI: 10.1038/s12276-022-00750-y -
Nature Structural & Molecular Biology Feb 2023DNA-dependent protein kinase (DNA-PK), a multicomponent complex including the DNA-PK catalytic subunit and Ku70/80 heterodimer together with DNA, is central to human DNA...
DNA-dependent protein kinase (DNA-PK), a multicomponent complex including the DNA-PK catalytic subunit and Ku70/80 heterodimer together with DNA, is central to human DNA damage response and repair. Using a DNA-PK-selective inhibitor (M3814), we identified from one dataset two cryo-EM structures of the human DNA-PK complex in different states, the intermediate state and the active state. Here we show that activation of the kinase is regulated through conformational changes caused by the binding ligand and the string region (residues 802-846) of the DNA-PK catalytic subunit, particularly the helix-hairpin-helix motif (residues 816-836) that interacts with DNA. These observations demonstrate the regulatory role of the ligand and explain why DNA-PK is DNA dependent. Cooperation and coordination among binding partners, disordered flexible regions and mechanically flexible HEAT repeats modulate the activation of the kinase. Together with previous findings, these results provide a better molecular understanding of DNA-PK catalysis.
Topics: Humans; DNA-Activated Protein Kinase; Protein Serine-Threonine Kinases; DNA-Binding Proteins; Phosphorylation; Ligands; Nuclear Proteins; Protein Kinases; DNA; DNA Repair; Antigens, Nuclear
PubMed: 36604499
DOI: 10.1038/s41594-022-00881-w