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Medicinal Research Reviews Mar 2017Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved... (Review)
Review
Kinase inhibitor research is a comparatively recent branch of medicinal chemistry and pharmacology and the first small-molecule kinase inhibitor, imatinib, was approved for clinical use only 15 years ago. Since then, 33 more kinase inhibitor drugs have received regulatory approval for the treatment of a variety of cancers and the volume of reports on the discovery and development of kinase inhibitors has increased to an extent where it is now difficult-even for those working in the field-easily to keep an overview of the compounds that are being developed, as currently there are 231 such compounds, targeting 38 different protein and lipid kinases (not counting isoforms), in clinical use or under clinical investigation. The purpose of this review is thus to provide an overview of the biomedical rationales for the kinases being targeted on the one hand, and the design principles, as well as chemical, pharmacological, pharmaceutical, and toxicological kinase inhibitor properties, on the other hand. Two issues that are especially important in kinase inhibitor research, target selectivity and drug resistance, as well as the underlying structural concepts, are discussed in general terms and in the context of relevant kinases and their inhibitors.
Topics: Animals; Humans; Inhibitory Concentration 50; Kinetics; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Kinases; Small Molecule Libraries
PubMed: 27775829
DOI: 10.1002/med.21409 -
ACS Chemical Biology Jan 2015The quest for ever more selective kinase inhibitors as potential future drugs has yielded a large repertoire of chemical probes that are selective for specific kinase... (Review)
Review
The quest for ever more selective kinase inhibitors as potential future drugs has yielded a large repertoire of chemical probes that are selective for specific kinase conformations. These probes have been useful tools to obtain structural snapshots of kinase conformational plasticity. Similarly, kinetic and thermodynamic inhibitor binding experiments provide glimpses at the time scales and energetics of conformational interconversions. These experimental insights are complemented by computational predictions of conformational energy landscapes and simulations of conformational transitions and of the process of inhibitors binding to the protein kinase domain. A picture emerges in which highly selective inhibitors capitalize on the dynamic nature of kinases.
Topics: Animals; Computational Biology; Humans; Ligands; Models, Molecular; Protein Binding; Protein Conformation; Protein Kinase Inhibitors; Protein Kinases; Substrate Specificity
PubMed: 25486330
DOI: 10.1021/cb500870a -
IUBMB Life Jun 2020The faithful propagation of cellular signals in most organisms relies on the coordinated functions of a large family of protein kinases that share a conserved catalytic... (Review)
Review
The faithful propagation of cellular signals in most organisms relies on the coordinated functions of a large family of protein kinases that share a conserved catalytic domain. The catalytic domain is a dynamic scaffold that undergoes large conformational changes upon activation. Most of these conformational changes, such as movement of the regulatory αC-helix from an "out" to "in" conformation, hinge on a conserved, but understudied, loop termed the αC-β4 loop, which mediates conserved interactions to tether flexible structural elements to the kinase core. We previously showed that the αC-β4 loop is a unique feature of eukaryotic protein kinases. Here, we review the emerging roles of this loop in kinase structure, function, regulation, and diseases. Through a kinome-wide analysis, we define the boundaries of the loop for the first time and show that sequence and structural variation in the loop correlate with conformational and regulatory variation. Many recurrent disease mutations map to the αC-β4 loop and contribute to drug resistance and abnormal kinase activation by relieving key auto-inhibitory interactions associated with αC-helix and inter-lobe movement. The αC-β4 loop is a hotspot for post-translational modifications, protein-protein interaction, and Hsp90 mediated folding. Our kinome-wide analysis provides insights for hypothesis-driven characterization of understudied kinases and the development of allosteric protein kinase inhibitors.
Topics: Amino Acid Motifs; Drug Resistance, Neoplasm; Evolution, Molecular; Humans; Mutation; Protein Conformation; Protein Interaction Domains and Motifs; Protein Kinases; Protein Processing, Post-Translational
PubMed: 32101380
DOI: 10.1002/iub.2253 -
Seminars in Cell & Developmental Biology Jan 2021Receptor Interacting Protein Kinases (RIPKs) are a family of Ser/Thr/Tyr kinases whose functions, regulation and pathophysiologic roles have remained an enigma for a... (Review)
Review
Receptor Interacting Protein Kinases (RIPKs) are a family of Ser/Thr/Tyr kinases whose functions, regulation and pathophysiologic roles have remained an enigma for a long time. In recent years, these proteins garnered significant interest due to their roles in regulating a variety of host defense functions including control of inflammatory gene expression, different forms of cell death, and cutaneous and intestinal barrier functions. In addition, there is accumulating evidence that while these kinases seemingly follow typical kinase blueprints, their functioning in cells can take forms that are atypical for protein kinases. Lastly, while these kinases generally belong to distinct areas of innate immune regulation, there are emerging overarching themes that may unify the functions of this kinase family. Our review seeks to discuss the biology of RIPKs, and how typical and atypical features of this family informs the activity of a rapidly growing repertoire of RIPK inhibitors.
Topics: Humans; Protein Kinases; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 32732131
DOI: 10.1016/j.semcdb.2020.06.014 -
Pharmacological Research Jun 2019Because mutations, overexpression, and dysregulation of protein kinases play essential roles in the pathogenesis of many illnesses, this enzyme family has become one of... (Review)
Review
Because mutations, overexpression, and dysregulation of protein kinases play essential roles in the pathogenesis of many illnesses, this enzyme family has become one of the most important drug targets in the past 20 years. The US FDA has approved 48 small molecule protein kinase inhibitors, nearly all of which are orally effective with the exceptions of netarsudil (which is given as an eye drop) and temsirolimus (which is given intravenously). Of the 48 approved drugs, the majority (25) target receptor protein-tyrosine kinases, ten target non-receptor protein-tyrosine kinases, and 13 target protein-serine/threonine protein kinases. The data indicate that 43 of these drugs are used in the treatment of malignancies (36 against solid tumors including lymphomas and seven against non-solid tumors, e.g., leukemias). Seven drugs are used in the treatment of non-malignancies: baricitinib, rheumatoid arthritis; fostamatinib, chronic immune thrombocytopenia; ruxolitinib, myelofibrosis and polycythemia vera; nintedanib, idiopathic pulmonary fibrosis; sirolimus, renal graft vs. host disease; netarsudil, glaucoma; tofacitinib, rheumatoid arthritis, Crohn disease, and ulcerative colitis. Moreover, ibrutinib and sirolimus are used for the treatment of both malignant and non-malignant diseases. The most common drug targets include ALK, B-Raf, BCR-Abl, epidermal growth factor receptor (EGFR), and vascular endothelial growth factor receptor (VEGFR). Most of the small molecule inhibitors (45) interact directly with the protein kinase domain. In contrast, sirolimus, temsirolimus, and everolimus are larger molecules (MW ≈ 1000) that bind to FKBP-12 to generate a complex that inhibits mTOR (mammalian target of rapamycin). This review presents the available drug-enzyme X-ray crystal structures for 27 of the approved drugs as well as the chemical structures and physicochemical properties of all of the FDA-approved small molecule protein kinase antagonists. Six of the drugs bind covalently and irreversibly to their target. Twenty of the 48 drugs have molecular weights greater than 500, exceeding a Lipinski rule of five criterion. Excluding the macrolides (everolimus, sirolimus, temsirolimus), the average molecular weight of drugs is 480 with a range of 306 (ruxolitinib) to 615 (trametinib). Nearly half of the antagonists (23) have a lipophilic efficiency with values of less than five while the recommended optima range from 5-10. One of the vexing problems is the near universal development of resistance that is associated with the use of small molecule protein kinase inhibitors for the treatment of cancer.
Topics: Animals; Crystallography, X-Ray; Drug Approval; Humans; Models, Molecular; Molecular Targeted Therapy; Protein Conformation; Protein Kinase Inhibitors; Protein Kinases; Small Molecule Libraries; United States; United States Food and Drug Administration
PubMed: 30877063
DOI: 10.1016/j.phrs.2019.03.006 -
The FEBS Journal Oct 2015Checkpoint kinase 1 (Chk1) is a master regulator of the DNA damage and replication checkpoints in vertebrate cells. When activated via phosphorylation by its upstream... (Review)
Review
Checkpoint kinase 1 (Chk1) is a master regulator of the DNA damage and replication checkpoints in vertebrate cells. When activated via phosphorylation by its upstream regulatory kinase, ATR, Chk1 prevents cells with damaged or incompletely replicated DNA from entering mitosis, and acts to stabilize stalled replication forks and suppress replication origin firing when DNA synthesis is inhibited. Chk1 blocks mitosis by maintaining high levels of inhibitory tyrosine phosphorylation of the mitotic cyclin-dependent kinase 1; however, the mechanisms that underlie replication fork stabilization and suppression of origin firing are less well defined. Although Chk1 function is evidently acutely regulated during these responses, how this occurs at the molecular level is incompletely understood. Recent evidence that Chk1 contains a 'kinase-associated 1' domain within its regulatory C-terminal region promises new insights. Additional modifications catalysed by other protein kinases, such as cyclin-dependent kinase 1, Akt, and RSK, can combine with ubiquitylation to regulate Chk1 subcellular localization and protein stability. Interestingly, it is clear that Chk1 has less well-defined functions in homologous recombination, chromatin modification, gene expression, spindle checkpoint proficiency, and cytokinesis. Here, we provide an overview of Chk1 regulation and functions, with an emphasis on unresolved questions that merit further research.
Topics: Checkpoint Kinase 1; DNA Damage; DNA Replication; Enzyme Activation; Genomic Instability; Mitosis; Protein Kinases; Protein Structure, Tertiary
PubMed: 26216057
DOI: 10.1111/febs.13387 -
Expert Opinion on Drug Discovery Dec 2019: Protein kinases are a major target for small-molecule drug development. However, relatively few compounds are free of off-target toxicity and reach the clinic. Because... (Review)
Review
: Protein kinases are a major target for small-molecule drug development. However, relatively few compounds are free of off-target toxicity and reach the clinic. Because the 500-plus kinases share conserved ATP-binding clefts, the site targeted by competitive inhibitors, generation of specific therapeutics remains a nearly intractable challenge. : Inducing degradation, instead of inhibition by occupancy-driven drugs, is an emerging strategy that offers the long-sought specificity, as well as mechanistic benefits. Currently approved inhibitors require steady-state binding and leave proteins intact for interactions in multi-protein complexes. After a general background about induced protein degradation, perspectives on protein kinases are provided. : Induced degradation by state-of-the-art compounds (proteolysis-targeting chimeras, PROTACs) has been shown for protein kinases, albeit in early pre-clinical stages. Further work is required to expand the number of enzymes that could be exploited to direct proteins for degradation by ubiquitylation. In addition, despite the simple modularity of the chimeras, generation of hits will require empirical approaches due to the role of protein-protein interactions and distribution of tagging sites. However, given the advantages of degradation, drug discovery efforts targeting protein kinases should increasingly shift toward generation and screening of inducers of degradation and away from occupancy-based inhibitors of old.
Topics: Animals; Drug Design; Drug Development; Drug Discovery; Humans; Protein Kinase Inhibitors; Protein Kinases; Proteins; Proteolysis; Small Molecule Libraries
PubMed: 31513432
DOI: 10.1080/17460441.2019.1660641 -
British Journal of Pharmacology Jun 2015Many human malignancies are associated with aberrant regulation of protein or lipid kinases due to mutations, chromosomal rearrangements and/or gene amplification.... (Review)
Review
Many human malignancies are associated with aberrant regulation of protein or lipid kinases due to mutations, chromosomal rearrangements and/or gene amplification. Protein and lipid kinases represent an important target class for treating human disorders. This review focus on 'the 10 things you should know about protein kinases and their inhibitors', including a short introduction on the history of protein kinases and their inhibitors and ending with a perspective on kinase drug discovery. Although the '10 things' have been, to a certain extent, chosen arbitrarily, they cover in a comprehensive way the past and present efforts in kinase drug discovery and summarize the status quo of the current kinase inhibitors as well as knowledge about kinase structure and binding modes. Besides describing the potentials of protein kinase inhibitors as drugs, this review also focus on their limitations, particularly on how to circumvent emerging resistance against kinase inhibitors in oncological indications.
Topics: Antineoplastic Agents; Drug Discovery; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Kinases
PubMed: 25630872
DOI: 10.1111/bph.13096 -
The Biochemical Journal Jan 2015Protein phosphorylation lies at the heart of cell signalling, and somatic mutation(s) in kinases drives and sustains a multitude of human diseases, including cancer. The... (Review)
Review
Protein phosphorylation lies at the heart of cell signalling, and somatic mutation(s) in kinases drives and sustains a multitude of human diseases, including cancer. The human protein kinase superfamily (the kinome) encodes approximately 50 'pseudokinases', which were initially predicted to be incapable of dynamic cell signalling when compared with canonical enzymatically active kinases. This assumption was supported by bioinformatics, which showed that amino acid changes at one or more key loci, making up the nucleotide-binding site or phosphotransferase machinery, were conserved in multiple vertebrate and non-vertebrate pseudokinase homologues. Protein kinases are highly attractive targets for drug discovery, as evidenced by the approval of almost 30 kinase inhibitors in oncology, and the successful development of the dual JAK1/2 (Janus kinase 1/2) inhibitor ruxolitinib for inflammatory indications. However, for such a large (>550) protein family, a remarkable number have still not been analysed at the molecular level, and only a surprisingly small percentage of kinases have been successfully targeted clinically. This is despite evidence that many are potential candidates for the development of new therapeutics. Indeed, several recent reports confirm that disease-associated pseudokinases can bind to nucleotide co-factors at concentrations achievable in the cell. Together, these findings suggest that drug targeting using either ATP-site or unbiased ligand-discovery approaches should now be attempted using the validation technology currently employed to evaluate their classic protein kinase counterparts. In the present review, we discuss members of the human pseudokinome repertoire, and catalogue somatic amino acid pseudokinase mutations that are emerging as the depth and clinical coverage of the human cancer pseudokinome expand.
Topics: Drug Delivery Systems; Genetic Loci; Humans; Neoplasm Proteins; Neoplasms; Nitriles; Protein Kinase Inhibitors; Protein Kinases; Proteome; Pyrazoles; Pyrimidines
PubMed: 25559089
DOI: 10.1042/BJ20141060 -
Nature Communications Aug 2021Dietary interventions such as intermittent fasting (IF) have emerged as an attractive strategy for cancer therapies; therefore, understanding the underlying molecular...
Dietary interventions such as intermittent fasting (IF) have emerged as an attractive strategy for cancer therapies; therefore, understanding the underlying molecular mechanisms is pivotal. Here, we find SIRT7 decline markedly attenuates the anti-tumor effect of IF. Mechanistically, AMP-activated protein kinase (AMPK) phosphorylating SIRT7 at T263 triggers further phosphorylation at T255/S259 by glycogen synthase kinase 3β (GSK3β), which stabilizes SIRT7 by decoupling E3 ligase UBR5. SIRT7 hyperphosphorylation achieves anti-tumor activity by disrupting the SKP2-SCF E3 ligase, thus preventing SKP2-mediated K63-linked AKT polyubiquitination and subsequent activation. In contrast, GSK3β-SIRT7 axis is inhibited by EGF/ERK2 signaling, with ERK2 inactivating GSK3β, thus accelerating SIRT7 degradation. Unfavorably, glucose deprivation or chemotherapy hijacks the GSK3β-SIRT7 axis via ERK2, thus activating AKT and ensuring survival. Notably, Trametinib, an FDA-approved MEK inhibitor, enhances the efficacy of combination therapy with doxorubicin and IF. Overall, we have revealed the GSK3β-SIRT7 axis that must be fine-tuned in the face of the energetic and oncogenic stresses in malignancy.
Topics: AMP-Activated Protein Kinase Kinases; Animals; Combined Modality Therapy; Doxorubicin; Fasting; Female; Glycogen Synthase Kinase 3 beta; Humans; Male; Mice; Mice, Inbred BALB C; Mitogen-Activated Protein Kinase 1; Neoplasms; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Proteolysis; Sirtuins
PubMed: 34433808
DOI: 10.1038/s41467-021-25274-3