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Trends in Pharmacological Sciences Jul 2015Kinases have emerged as one of the most intensively pursued targets in current pharmacological research, especially for cancer, due to their critical roles in cellular... (Review)
Review
Kinases have emerged as one of the most intensively pursued targets in current pharmacological research, especially for cancer, due to their critical roles in cellular signaling. To date, the US FDA has approved 28 small-molecule kinase inhibitors, half of which were approved in the past 3 years. While the clinical data of these approved molecules are widely presented and structure-activity relationship (SAR) has been reported for individual molecules, an updated review that analyzes all approved molecules and summarizes current achievements and trends in the field has yet to be found. Here we present all approved small-molecule kinase inhibitors with an emphasis on binding mechanism and structural features, summarize current challenges, and discuss future directions in this field.
Topics: Drug Approval; Enzyme Inhibitors; Models, Molecular; Molecular Structure; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Phosphotransferases; Protein Binding; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Receptor Protein-Tyrosine Kinases; United States; United States Food and Drug Administration
PubMed: 25975227
DOI: 10.1016/j.tips.2015.04.005 -
Nature Dec 2021The liberation of energy stores from adipocytes is critical to support survival in times of energy deficit; however, uncontrolled or chronic lipolysis associated with...
The liberation of energy stores from adipocytes is critical to support survival in times of energy deficit; however, uncontrolled or chronic lipolysis associated with insulin resistance and/or insulin insufficiency disrupts metabolic homeostasis. Coupled to lipolysis is the release of a recently identified hormone, fatty-acid-binding protein 4 (FABP4). Although circulating FABP4 levels have been strongly associated with cardiometabolic diseases in both preclinical models and humans, no mechanism of action has yet been described. Here we show that hormonal FABP4 forms a functional hormone complex with adenosine kinase (ADK) and nucleoside diphosphate kinase (NDPK) to regulate extracellular ATP and ADP levels. We identify a substantial effect of this hormone on beta cells and given the central role of beta-cell function in both the control of lipolysis and development of diabetes, postulate that hormonal FABP4 is a key regulator of an adipose-beta-cell endocrine axis. Antibody-mediated targeting of this hormone complex improves metabolic outcomes, enhances beta-cell function and preserves beta-cell integrity to prevent both type 1 and type 2 diabetes. Thus, the FABP4-ADK-NDPK complex, Fabkin, represents a previously unknown hormone and mechanism of action that integrates energy status with the function of metabolic organs, and represents a promising target against metabolic disease.
Topics: Adipocytes; Diabetes Mellitus; Fatty Acid-Binding Proteins; Humans; Insulin; Islets of Langerhans; Lipolysis; Nucleosides; Phosphotransferases
PubMed: 34880500
DOI: 10.1038/s41586-021-04137-3 -
Nature Communications Sep 2014Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered...
Human cancer genomes harbour a variety of alterations leading to the deregulation of key pathways in tumour cells. The genomic characterization of tumours has uncovered numerous genes recurrently mutated, deleted or amplified, but gene fusions have not been characterized as extensively. Here we develop heuristics for reliably detecting gene fusion events in RNA-seq data and apply them to nearly 7,000 samples from The Cancer Genome Atlas. We thereby are able to discover several novel and recurrent fusions involving kinases. These findings have immediate clinical implications and expand the therapeutic options for cancer patients, as approved or exploratory drugs exist for many of these kinases.
Topics: Gene Expression Profiling; Gene Fusion; Genome, Human; Humans; Molecular Targeted Therapy; Neoplasms; Phosphotransferases; Sequence Analysis, RNA
PubMed: 25204415
DOI: 10.1038/ncomms5846 -
Current Biology : CB Mar 2018Cells maintain integrity despite changes in their mechanical properties elicited during growth and environmental stress. How cells sense their physical state and...
Cells maintain integrity despite changes in their mechanical properties elicited during growth and environmental stress. How cells sense their physical state and compensate for cell-wall damage is poorly understood, particularly in plants. Here we report that FERONIA (FER), a plasma-membrane-localized receptor kinase from Arabidopsis, is necessary for the recovery of root growth after exposure to high salinity, a widespread soil stress. The extracellular domain of FER displays tandem regions of homology with malectin, an animal protein known to bind di-glucose in vitro and important for protein quality control in the endoplasmic reticulum. The presence of malectin-like domains in FER and related receptor kinases has led to widespread speculation that they interact with cell-wall polysaccharides and can potentially serve a wall-sensing function. Results reported here show that salinity causes softening of the cell wall and that FER is necessary to sense these defects. When this function is disrupted in the fer mutant, root cells explode dramatically during growth recovery. Similar defects are observed in the mur1 mutant, which disrupts pectin cross-linking. Furthermore, fer cell-wall integrity defects can be rescued by treatment with calcium and borate, which also facilitate pectin cross-linking. Sensing of these salinity-induced wall defects might therefore be a direct consequence of physical interaction between the extracellular domain of FER and pectin. FER-dependent signaling elicits cell-specific calcium transients that maintain cell-wall integrity during salt stress. These results reveal a novel extracellular toxicity of salinity, and identify FER as a sensor of damage to the pectin-associated wall.
Topics: Arabidopsis; Arabidopsis Proteins; Calcium Signaling; Cell Wall; Phosphotransferases; Salt Stress
PubMed: 29456142
DOI: 10.1016/j.cub.2018.01.023 -
Cell Chemical Biology Jan 2018New opportunities to advance small-molecule kinase ligands that downregulate their cognate target binding proteins are discussed. Rationally designed heterobifunctional... (Review)
Review
New opportunities to advance small-molecule kinase ligands that downregulate their cognate target binding proteins are discussed. Rationally designed heterobifunctional kinase degraders are compared with ATP site ligands that were serendipitously found to cause kinase downregulation. These approaches could be particularly useful in the treatment of cancers since many kinases are known to remodel pro-oncogenic protein-protein interactions, which could be destroyed by small-molecule-mediated kinase depletion.
Topics: Down-Regulation; Humans; Ligands; Phosphotransferases; Protein Kinase Inhibitors
PubMed: 29174540
DOI: 10.1016/j.chembiol.2017.10.011 -
ELife Dec 2023Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Why does protein kinase A respond to purine nucleosides in certain pathogens, but not to the cyclic nucleotides that activate this kinase in most other organisms?
Topics: Leishmania donovani; Ligands; Phosphotransferases; Cyclic AMP-Dependent Protein Kinases; Purine Nucleosides; Trypanosoma brucei brucei
PubMed: 38126364
DOI: 10.7554/eLife.94720 -
ChemMedChem Apr 2021Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug-like compounds on any site, can give important stimuli to... (Review)
Review
Understanding the ligandability of a target protein, defined as the capability of a protein to bind drug-like compounds on any site, can give important stimuli to drug-development projects. For instance, inhibition of protein-protein interactions usually depends on the identification of protein surface binders. DNA-encoded chemical libraries (DELs) allow scanning of protein surfaces with large chemical space. Encoded library selection screens uncovered several protein-protein interaction inhibitors and compounds binding to the surface of G protein-coupled receptors (GPCRs) and kinases. The protein surface-binding chemotypes from DELs are predominantly chemically modified and cyclized peptides, and functional small-molecule peptidomimetics. Peptoid libraries and structural peptidomimetics have been less studied in the DEL field, hinting at hitherto less populated chemical space and suggesting alternative library designs. Roughly a third of bioactive molecules evolved from smaller, target-focused libraries. They showcase the potential of encoded libraries to identify more potent molecules from weak, for example, fragment-like, starting points.
Topics: DNA; Humans; Phosphotransferases; Protein Binding; Receptors, G-Protein-Coupled; Small Molecule Libraries; Surface Properties
PubMed: 33295694
DOI: 10.1002/cmdc.202000869 -
Chemical Society Reviews May 2020Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords a unique set of advantages as well as challenges... (Review)
Review
Over the past decade, covalent kinase inhibitors (CKI) have seen a resurgence in drug discovery. Covalency affords a unique set of advantages as well as challenges relative to their non-covalent counterpart. After reversible protein target recognition and binding, covalent inhibitors irreversibly modify a proximal nucleophilic residue on the protein via reaction with an electrophile. To date, the acrylamide group remains the predominantly employed electrophile in CKI development, with its incorporation in the majority of clinical candidates and FDA approved covalent therapies. Nonetheless, in recent years considerable efforts have ensued to characterize alternative electrophiles that exhibit irreversible or reversibly covalent binding mechanisms towards cysteine thiols and other amino acids. This review article provides a comprehensive overview of CKIs reported in the literature over a decade period, 2007-2018. Emphasis is placed on the rationale behind warhead choice, optimization approach, and inhibitor design. Current FDA approved CKIs are also highlighted, in addition to a detailed analysis of the common trends and themes observed within the listed data set.
Topics: Binding Sites; Drug Discovery; Enzyme Inhibitors; Models, Molecular; Phosphotransferases; Protein Conformation
PubMed: 32227030
DOI: 10.1039/c9cs00720b -
Journal of Molecular Microbiology and... 2015The acetone-butanol-ethanol fermentation employing solventogenic clostridia was a major industrial process during the 20th century, but declined for economic reasons. In... (Review)
Review
The acetone-butanol-ethanol fermentation employing solventogenic clostridia was a major industrial process during the 20th century, but declined for economic reasons. In recent times, interest in the process has been revived due to the perceived potential of butanol as a superior biofuel. Redevelopment of an efficient fermentation process will require a detailed understanding of the physiology of carbohydrate utilization by the bacteria. Genome sequences have revealed that, as in other anaerobes, the phosphotransferase system (PTS) and associated regulatory functions are likely to play an important role in sugar uptake and its regulation. The genomes of Clostridium acetobutylicum and C. beijerinckii encode 13 and 43 phosphotransferases, respectively. Characterization of clostridial phosphotransferases has demonstrated that they are involved in the uptake and phosphorylation of hexoses, hexose derivatives and disaccharides, although the functions of many systems remain to be determined. Glucose is a dominant sugar which represses the utilization of other carbon sources, including the non-PTS pentose sugars xylose and arabinose, by the clostridia. Targeting of the CcpA-dependent mechanism of carbon catabolite repression has been shown to be an effective strategy for reducing the repressive effects of glucose, indicating potential for developing strains with improved fermentation performance.
Topics: Acetone; Biofuels; Butanols; Catabolite Repression; Clostridium; Clostridium acetobutylicum; Clostridium beijerinckii; Ethanol; Fermentation; Glucose; Phosphotransferases; Phylogeny; Sequence Alignment; Xylose
PubMed: 26159074
DOI: 10.1159/000375125 -
The Journal of Biological Chemistry Apr 2023The cytidine diphosphate-choline (Kennedy) pathway culminates with the synthesis of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) by choline/ethanolamine...
The cytidine diphosphate-choline (Kennedy) pathway culminates with the synthesis of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) by choline/ethanolamine phosphotransferase 1 (CEPT1) in the endoplasmic reticulum (ER), and PC synthesis by choline phosphotransferase 1 (CHPT1) in the Golgi apparatus. Whether the PC and PE synthesized by CEPT1 and CHPT1 in the ER and Golgi apparatus has different cellular functions has not been formally addressed. Here, we used CRISPR editing to generate CEPT1-and CHPT1-KO U2OS cells to assess the differential contribution of the enzymes to feedback regulation of nuclear CTP:phosphocholine cytidylyltransferase (CCT)α, the rate-limiting enzyme in PC synthesis, and lipid droplet (LD) biogenesis. We found that CEPT1-KO cells had a 50 and 80% reduction in PC and PE synthesis, respectively, while PC synthesis in CHPT1-KO cells was also reduced by 50%. CEPT1 KO caused the posttranscriptional induction of CCTα protein expression as well as its dephosphorylation and constitutive localization on the inner nuclear membrane and nucleoplasmic reticulum. This activated CCTα phenotype was prevented by incubating CEPT1-KO cells with PC liposomes to restore end-product inhibition. Additionally, we determined that CEPT1 was in close proximity to cytoplasmic LDs and CEPT1 KO resulted in the accumulation of small cytoplasmic LDs, as well as increased nuclear LDs enriched in CCTα. In contrast, CHPT1 KO had no effect on CCTα regulation or LD biogenesis. Thus, CEPT1 and CHPT1 contribute equally to PC synthesis; however, only PC synthesized by CEPT1 in the ER regulates CCTα and the biogenesis of cytoplasmic and nuclear LDs.
Topics: Phosphatidylcholines; Lipid Droplets; Phosphotransferases; Homeostasis; Choline; Choline-Phosphate Cytidylyltransferase
PubMed: 36871755
DOI: 10.1016/j.jbc.2023.104578