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Journal of Medicinal Chemistry May 2022
Topics: Protein Kinase Inhibitors; Protein Kinases
PubMed: 35512193
DOI: 10.1021/acs.jmedchem.2c00623 -
Molecular Cancer Feb 2018The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated... (Review)
Review
The human genome encodes 538 protein kinases that transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are associated with human cancer initiation and progression. The recent development of small-molecule kinase inhibitors for the treatment of diverse types of cancer has proven successful in clinical therapy. Significantly, protein kinases are the second most targeted group of drug targets, after the G-protein-coupled receptors. Since the development of the first protein kinase inhibitor, in the early 1980s, 37 kinase inhibitors have received FDA approval for treatment of malignancies such as breast and lung cancer. Furthermore, about 150 kinase-targeted drugs are in clinical phase trials, and many kinase-specific inhibitors are in the preclinical stage of drug development. Nevertheless, many factors confound the clinical efficacy of these molecules. Specific tumor genetics, tumor microenvironment, drug resistance, and pharmacogenomics determine how useful a compound will be in the treatment of a given cancer. This review provides an overview of kinase-targeted drug discovery and development in relation to oncology and highlights the challenges and future potential for kinase-targeted cancer therapies.
Topics: Animals; Humans; Molecular Structure; Neoplasms; Protein Kinase Inhibitors; Protein Kinases
PubMed: 29455673
DOI: 10.1186/s12943-018-0804-2 -
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 Oct 2014The ability of protein kinases to switch between inactive and active states is critical to control the outputs of cellular signaling pathways. In several protein... (Review)
Review
The ability of protein kinases to switch between inactive and active states is critical to control the outputs of cellular signaling pathways. In several protein kinases, the conformation of helix αC is a key hub on which regulatory inputs converge to induce catalytic switching. An emerging mechanism involved in regulating helix αC orientation is the allosteric coupling with kinase domain surfaces involved in homo- or heterodimerization. In this review, we discuss dimerization-mediated regulation of the rapidly accelerated fibrosarcoma (RAF) and eIF2α kinase families and draw parallels with the analogous behavior of the epidermal growth factor receptor (EGFR) and serine/threonine-protein kinase endoribonuclease 1 (IRE1)/ribonuclease L (RNAse L) kinase families. Given that resistance to RAF-targeted therapeutics often stems from dimerization-dependent mechanisms, we suggest that a better understanding of dimerization-induced allostery may assist in developing alternate therapeutic strategies.
Topics: Allosteric Regulation; Endoribonucleases; Enzyme Activation; Gene Expression Regulation, Enzymologic; Humans; Models, Molecular; Phosphorylation; Protein Conformation; Protein Kinases; Protein Multimerization; Protein Serine-Threonine Kinases; Protein Structure, Quaternary; Protein Structure, Tertiary; Signal Transduction; raf Kinases
PubMed: 25220378
DOI: 10.1016/j.tibs.2014.08.004 -
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 -
Biochimica Et Biophysica Acta Oct 2015Due to their involvement in human diseases, protein kinases are an important therapeutic target class. Conformation is a key concept for understanding how functional... (Review)
Review
Due to their involvement in human diseases, protein kinases are an important therapeutic target class. Conformation is a key concept for understanding how functional activity, inhibition and sequence are linked. We assemble and annotate the mammalian structural kinome from the Protein Data Bank on the basis of a universal residue nomenclature. We identify a torsion angle around the Gly of the DFG-motif whose sharp distribution profile corresponds to three eclipsed conformations. This allows the definition a small set of clusters whose distribution shows a bias for the active conformation. A common rationale links the active and inactive state: stabilization of the active conformation, as well as inactivation by displacement of helix-αC or the DFG-motif is governed by the interaction between helix-αC and the DFG motif. In particular, the conformation of the DFG-motif is tightly correlated with the propensity of helix-αC displacement. Our analysis reveals detailed mechanisms for the displacement of helix-αC and the DFG and improves our understanding of the role of individual residues. By pooling conformations from the whole structural kinome, the energetic contributions of sequence and extrinsic factors can be estimated in free energy analyses. This article is part of a Special Issue entitled: Inhibitors of Protein Kinases.
Topics: Amino Acid Motifs; Animals; Databases, Protein; Humans; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Protein Kinases; Thermodynamics
PubMed: 25839999
DOI: 10.1016/j.bbapap.2015.03.009 -
Cell Structure and Function 2015Checkpoint kinase 1 (Chk1) is a conserved protein kinase central to the cell-cycle checkpoint during DNA damage response (DDR). Until recently, ATR, a protein kinase... (Review)
Review
Checkpoint kinase 1 (Chk1) is a conserved protein kinase central to the cell-cycle checkpoint during DNA damage response (DDR). Until recently, ATR, a protein kinase activated in response to DNA damage or stalled replication, has been considered as the sole regulator of Chk1. Recent progress, however, has led to the identification of additional protein kinases involved in Chk1 phosphorylation, affecting the subcellular localization and binding partners of Chk1. In fact, spatio-temporal regulation of Chk1 is of critical importance not only in the DDR but also in normal cell-cycle progression. In due course, many potent inhibitors targeted to Chk1 have been developed as anticancer agents and some of these inhibitors are currently in clinical trials. In this review, we summarize the current knowledge of Chk1 regulation by phosphorylation.
Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Checkpoint Kinase 1; Cyclin-Dependent Kinases; Humans; Phosphorylation; Protein Kinases; Serine
PubMed: 25748360
DOI: 10.1247/csf.14017 -
Journal of Medicinal Chemistry Jan 2022Allosteric kinase inhibitors are thought to have high selectivity and are prime candidates for kinase drug discovery. In addition, the exploration of allosteric... (Review)
Review
Allosteric kinase inhibitors are thought to have high selectivity and are prime candidates for kinase drug discovery. In addition, the exploration of allosteric mechanisms represents an attractive topic for basic research and drug design. Although the identification and characterization of allosteric kinase inhibitors is still far from being routine, X-ray structures of kinase complexes have been determined for a significant number of such inhibitors. On the basis of structural data, allosteric inhibitors can be confirmed. We report a comprehensive survey of allosteric kinase inhibitors and activators from publicly available X-ray structures, map their binding sites, and determine their distribution over binding pockets in kinases. In addition, we discuss structural features of these compounds and identify active structural analogues and high-confidence target annotations, indicating additional activities for a subset of allosteric inhibitors. This contribution aims to provide a detailed structure-based view of allosteric kinase inhibition.
Topics: Allosteric Regulation; Animals; Drug Design; Drug Discovery; Humans; Models, Molecular; Protein Conformation; Protein Kinase Inhibitors; Protein Kinases; Structure-Activity Relationship
PubMed: 33476146
DOI: 10.1021/acs.jmedchem.0c02076 -
Future Medicinal Chemistry Aug 2020
Topics: Drug Discovery; Humans; Ligands; Protein Kinase Inhibitors; Protein Kinases
PubMed: 32597212
DOI: 10.4155/fmc-2020-0118