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Pharmacological Research Feb 2024Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st... (Review)
Review
Owing to the dysregulation of protein kinase activity in many diseases including cancer, this enzyme family has become one of the most important drug targets in the 21st century. There are 80 FDA-approved therapeutic agents that target about two dozen different protein kinases and seven of these drugs were approved in 2023. Of the approved drugs, thirteen target protein-serine/threonine protein kinases, four are directed against dual specificity protein kinases (MEK1/2), twenty block nonreceptor protein-tyrosine kinases, and 43 inhibit receptor protein-tyrosine kinases. The data indicate that 69 of these drugs are prescribed for the treatment of neoplasms. Six drugs (abrocitinib, baricitinib, deucravacitinib, ritlecitinib, tofacitinib, upadacitinib) are used for the treatment of inflammatory diseases (atopic dermatitis, rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis). Of the 80 approved drugs, nearly two dozen are used in the treatment of multiple diseases. The following seven drugs received FDA approval in 2023: capivasertib (HER2-positive breast cancer), fruquintinib (metastatic colorectal cancer), momelotinib (myelofibrosis), pirtobrutinib (mantle cell lymphoma, chronic lymphocytic leukemia, small lymphocytic lymphoma), quizartinib (Flt3-mutant acute myelogenous leukemia), repotrectinib (ROS1-positive lung cancer), and ritlecitinib (alopecia areata). All of the FDA-approved drugs are orally effective with the exception of netarsudil, temsirolimus, and trilaciclib. This review summarizes the physicochemical properties of all 80 FDA-approved small molecule protein kinase inhibitors including the molecular weight, number of hydrogen bond donors/acceptors, polar surface area, potency, solubility, lipophilic efficiency, and ligand efficiency.
Topics: Humans; Adult; Protein Kinase Inhibitors; Alopecia Areata; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Protein Serine-Threonine Kinases; Protein Kinases; Neoplasms
PubMed: 38216005
DOI: 10.1016/j.phrs.2024.107059 -
International Journal of Molecular... Sep 2022Ca/calmodulin-dependent protein kinase kinase (CaMKK) is the activating kinase for multiple downstream kinases, including CaM-kinase I (CaMKI), CaM-kinase IV (CaMKIV),... (Review)
Review
Ca/calmodulin-dependent protein kinase kinase (CaMKK) is the activating kinase for multiple downstream kinases, including CaM-kinase I (CaMKI), CaM-kinase IV (CaMKIV), protein kinase B (PKB/Akt), and 5'AMP-kinase (AMPK), through the phosphorylation of their activation-loop Thr residues in response to increasing the intracellular Ca concentration, as CaMKK itself is a Ca/CaM-dependent enzyme. The CaMKK-mediated kinase cascade plays important roles in a number of Ca-dependent pathways, such as neuronal morphogenesis and plasticity, transcriptional activation, autophagy, and metabolic regulation, as well as in pathophysiological pathways, including cancer progression, metabolic syndrome, and mental disorders. This review focuses on the molecular mechanism underlying CaMKK-mediated signal transduction in normal and pathophysiological conditions. We summarize the current knowledge of the structural, functional, and physiological properties of the regulatory kinase, CaMKK, and the development and application of its pharmacological inhibitors.
Topics: AMP-Activated Protein Kinases; Adenosine Monophosphate; Calcium-Calmodulin-Dependent Protein Kinase Kinase; Calcium-Calmodulin-Dependent Protein Kinases; Humans; Phosphorylation; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 36232320
DOI: 10.3390/ijms231911025 -
Nature Reviews. Immunology Dec 2023Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death... (Review)
Review
Protein kinases play a major role in cellular activation processes, including signal transduction by diverse immunoreceptors. Given their roles in cell growth and death and in the production of inflammatory mediators, targeting kinases has proven to be an effective treatment strategy, initially as anticancer therapies, but shortly thereafter in immune-mediated diseases. Herein, we provide an overview of the status of small molecule inhibitors specifically generated to target protein kinases relevant to immune cell function, with an emphasis on those approved for the treatment of immune-mediated diseases. The development of inhibitors of Janus kinases that target cytokine receptor signalling has been a particularly active area, with Janus kinase inhibitors being approved for the treatment of multiple autoimmune and allergic diseases as well as COVID-19. In addition, TEC family kinase inhibitors (including Bruton's tyrosine kinase inhibitors) targeting antigen receptor signalling have been approved for haematological malignancies and graft versus host disease. This experience provides multiple important lessons regarding the importance (or not) of selectivity and the limits to which genetic information informs efficacy and safety. Many new agents are being generated, along with new approaches for targeting kinases.
Topics: Humans; Protein Kinases; Protein Kinase Inhibitors; Signal Transduction; Immune System Diseases
PubMed: 37188939
DOI: 10.1038/s41577-023-00877-7 -
International Journal of Molecular... Aug 2017Protein phosphorylation is an impo-rtant cellular regulatory mechanism as many enzymes and receptors are activated/deactivated by phosphorylation and dephosphorylation... (Review)
Review
Protein phosphorylation is an impo-rtant cellular regulatory mechanism as many enzymes and receptors are activated/deactivated by phosphorylation and dephosphorylation events, by means of kinases and phosph-atases. In particular, the protein kinases are responsible for cellular transduction signaling and their hyperactivity, malfunction or overexpression can be found in several diseases, mostly tumors. Therefore, it is evident that the use of kinase inhibitors can be valuable for the treatment of cancer. In this review, we discuss the mechanism of action of phosphorylation, with particular attention to the importance of phosphorylation under physiological and pathological conditions. We also discuss the possibility of using kinase inhibitors in the treatment of tumors.
Topics: Animals; Humans; Molecular Targeted Therapy; Neoplasms; Phosphoric Monoester Hydrolases; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction
PubMed: 28656226
DOI: 10.3892/ijmm.2017.3036 -
Cancer Gene Therapy Sep 2023Gastrointestinal cancers are a leading cause of cancer morbidity and mortality worldwide with 4.2 million new cases and 3.2 million deaths estimated in 2020. Despite the... (Review)
Review
Gastrointestinal cancers are a leading cause of cancer morbidity and mortality worldwide with 4.2 million new cases and 3.2 million deaths estimated in 2020. Despite the advances in primary and adjuvant therapies, patients still develop distant metastases and require novel therapies. Mitogen‑activated protein kinase (MAPK) cascades are crucial signaling pathways that regulate many cellular processes, including proliferation, differentiation, apoptosis, stress responses and cancer development. p38 Mitogen Activated Protein Kinases (p38 MAPKs) includes four isoforms: p38α (MAPK14), p38β (MAPK11), p38γ (MAPK12), and p38δ (MAPK13). p38 MAPK was first identified as a stress response protein kinase that phosphorylates different transcriptional factors. Dysregulation of p38 pathways, in particular p38γ, are associated with cancer development, metastasis, autophagy and tumor microenvironment. In this article, we provide an overview of p38 and p38γ with respect to gastrointestinal cancers. Furthermore, targeting p38γ is also discussed as a potential therapy for gastrointestinal cancers.
Topics: Humans; Mitogen-Activated Protein Kinase 11; Mitogen-Activated Protein Kinase 12; Mitogen-Activated Protein Kinase 13; Signal Transduction; Gastrointestinal Neoplasms; p38 Mitogen-Activated Protein Kinases; Tumor Microenvironment
PubMed: 37248432
DOI: 10.1038/s41417-023-00622-1 -
Science Advances Jul 2022Exposure to cold triggers a spike in cytosolic calcium (Ca) that often leads to transcriptional reprogramming in plants. However, how this Ca signal is perceived and...
Exposure to cold triggers a spike in cytosolic calcium (Ca) that often leads to transcriptional reprogramming in plants. However, how this Ca signal is perceived and relayed to the downstream cold signaling pathway remains unknown. Here, we show that the CALCIUM-DEPENDENT PROTEIN KINASE 28 (CPK28) initiates a phosphorylation cascade to specify transcriptional reprogramming downstream of cold-induced Ca signal. Plasma membrane (PM)-localized CPK28 is activated rapidly upon cold shock within 10 seconds in a Ca-dependent manner. CPK28 then phosphorylates and promotes the nuclear translocation of NIN-LIKE PROTEIN 7 (NLP7), a transcription factor that specifies the transcriptional reprogramming of gene sets in response to Ca, thereby positively regulating plant response to cold stress. This study elucidates a previously unidentified mechanism by which the CPK28-NLP7 regulatory module integrates cold-evoked Ca signal and transcriptome and thus uncovers a key strategy for the rapid perception and transduction of cold signals from the PM to the nucleus.
Topics: Arabidopsis; Arabidopsis Proteins; Gene Expression Regulation, Plant; Protein Kinases
PubMed: 35767615
DOI: 10.1126/sciadv.abn7901 -
Nature Dec 2020The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology, and more recently in...
The MAPK/ERK kinase MEK is a shared effector of the frequent cancer drivers KRAS and BRAF that has long been pursued as a drug target in oncology, and more recently in immunotherapy and ageing. However, many MEK inhibitors are limited owing to on-target toxicities and drug resistance. Accordingly, a molecular understanding of the structure and function of MEK within physiological complexes could provide a template for the design of safer and more effective therapies. Here we report X-ray crystal structures of MEK bound to the scaffold KSR (kinase suppressor of RAS) with various MEK inhibitors, including the clinical drug trametinib. The structures reveal an unexpected mode of binding in which trametinib directly engages KSR at the MEK interface. In the bound complex, KSR remodels the prototypical allosteric pocket of the MEK inhibitor, thereby affecting binding and kinetics, including the drug-residence time. Moreover, trametinib binds KSR-MEK but disrupts the related RAF-MEK complex through a mechanism that exploits evolutionarily conserved interface residues that distinguish these sub-complexes. On the basis of these insights, we created trametiglue, which limits adaptive resistance to MEK inhibition by enhancing interfacial binding. Our results reveal the plasticity of an interface pocket within MEK sub-complexes and have implications for the design of next-generation drugs that target the RAS pathway.
Topics: Amino Acid Sequence; Animals; Binding Sites; Humans; Mice; Mitogen-Activated Protein Kinase Kinases; Models, Molecular; Protein Binding; Protein Kinase Inhibitors; Protein Kinases; Pyridones; Pyrimidinones; Substrate Specificity; raf Kinases
PubMed: 32927473
DOI: 10.1038/s41586-020-2760-4 -
Trends in Parasitology Nov 2022Trypanosomatid parasitic protozoa are divergent from opisthokont models and have evolved unique mechanisms to regulate their complex life cycles and to adapt to a range... (Review)
Review
Trypanosomatid parasitic protozoa are divergent from opisthokont models and have evolved unique mechanisms to regulate their complex life cycles and to adapt to a range of hosts. Understanding how these organisms respond, adapt, and persist in their different hosts could reveal optimal drug-control strategies. Protein kinases are fundamental to many biological processes such as cell cycle control, adaptation to stress, and cellular differentiation. Therefore, we have focused this review on the features and functions of protein kinases that distinguish trypanosomatid kinomes from other eukaryotes. We describe the latest research, highlighting similarities and differences between two groups of trypanosomatid parasites, Leishmania and African trypanosomes.
Topics: Animals; Leishmania; Life Cycle Stages; Protein Kinases; Trypanosoma
PubMed: 36075845
DOI: 10.1016/j.pt.2022.08.009 -
ELife Aug 2019Predicting ancestral sequences of protein kinases reveals the molecular details that underlie different modes of activation.
Predicting ancestral sequences of protein kinases reveals the molecular details that underlie different modes of activation.
Topics: Protein Kinases
PubMed: 31407665
DOI: 10.7554/eLife.49976 -
Molecular Pharmacology Apr 2022Protein kinase A (PKA) is a holoenzyme consisting of a regulatory (R)-subunit dimer and two catalytic (C)-subunits. There are two major families of C-subunits, C and C,... (Review)
Review
Protein kinase A (PKA) is a holoenzyme consisting of a regulatory (R)-subunit dimer and two catalytic (C)-subunits. There are two major families of C-subunits, C and C, and four functionally nonredundant R-subunits (RI, RI, RII, RII). In addition to binding to and being regulated by the R-subunits, the C-subunits are regulated by two tail regions that each wrap around the N- and C-lobes of the kinase core. Although the C-terminal (Ct-) tail is classified as an intrinsically disordered region (IDR), the N-terminal (Nt-) tail is dominated by a strong helix that is flanked by short IDRs. In contrast to the Ct-tail, which is a conserved and highly regulated feature of all PKA, PKG, and protein kinase C protein kinase group (AGC) kinases, the Nt-tail has evolved more recently and is highly variable in vertebrates. Surprisingly and in contrast to the kinase core and the Ct-tail, the entire Nt-tail is not conserved in nonmammalian PKAs. In particular, in humans, C actually represents a large family of C-subunits that are highly variable in their Nt-tail and also expressed in a highly tissue-specific manner. Although we know so much about the C1-subunit, we know almost nothing about these C isoforms wherein C2 is highly expressed in lymphocytes, and C3 and C4 isoforms account for ∼50% of PKA signaling in brain. Based on recent disease mutations, the C proteins appear to be functionally important and nonredundant with the C isoforms. Imaging in retina also supports nonredundant roles for C as well as isoform-specific localization to mitochondria. This represents a new frontier in PKA signaling. SIGNIFICANCE STATEMENT: How tails and adjacent domains regulate each protein kinase is a fundamental challenge for the biological community. Here we highlight how the N- and C-terminal tails of PKA (Nt-tails/Ct-tails) affect the structure and regulate the function of the kinase core and show the combinatorial variations that are introduced into the Nt-tail of the C- and C-subunits in contrast to the Ct-tail, which is conserved across the entire AGC subfamily of protein kinases.
Topics: Animals; Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; Cyclic AMP-Dependent Protein Kinases; Humans; Protein Isoforms; Protein Kinases; Signal Transduction
PubMed: 34330820
DOI: 10.1124/molpharm.121.000315