scholarly journals Betulin, a Newly Characterized Compound in Acacia auriculiformis Bark, Is a Multi-Target Protein Kinase Inhibitor

Molecules ◽  
2021 ◽  
Vol 26 (15) ◽  
pp. 4599
Author(s):  
Augustine Ahmadu ◽  
Claire Delehouzé ◽  
Anas Haruna ◽  
Lukman Mustapha ◽  
Bilqis Lawal ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Growth Factor Receptor ◽  
Binding Pocket ◽  
Stem Bark ◽  
Janus Kinase ◽  
Myelogenous Leukemia ◽  
Acacia Auriculiformis

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from Acacia auriculiformis stem bark. Column chromatography and NMR spectroscopy were used to purify and characterize betulin from an ethyl acetate soluble fraction of acacia bark. Betulin, a known inducer of apoptosis, was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1ε (CK1ε), glycogen synthase kinase 3α/β (GSK-3 α/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6), and vascular endothelial growth factor receptor 2 kinase (VEGFR2) with activities in the micromolar range for each. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to investigate its putative use as an anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway, with activity similar to that of imatinib mesylate, a known ABL1 kinase inhibitor. The interaction of betulin and ABL1 was studied by molecular docking, revealing an interaction of the inhibitor with the ABL1 ATP binding pocket. Together, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and to potential treatments for leukemia.

scholarly journals Betulin, a Newly Characterized Compound in Acacia Auriculiformis Bark, is a Multi-target Protein Kinase Inhibitor

2021 ◽  
Author(s):  
Augustine A. Ahmadu ◽  
Claire Delehouzé ◽  
Anas Haruna ◽  
Lukman Mustapha ◽  
Bilqis A. Lawal ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Gel Filtration ◽  
Growth Factor Receptor ◽  
Stem Bark ◽  
Janus Kinase ◽  
Myelogenous Leukemia ◽  
Acacia Auriculiformis

The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from ethyl acetate soluble fraction of Acacia auriculiformis stem bark. Column chromatography, gel filtration and NMR spectroscopy were used to purified and characterized betulin from the extract. Betulin which is a known inducer of apoptosis was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1epsilon (CK1epsilon), glycogen synthase kinase 3alpha/β (GSK-3alpha/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6) and vascular endothelial growth factor receptor 2 kinase (VEGFR2) and with activity in µM range. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to underline its putative use as anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pathway similarly to imatinib mesylate, a well-known inhibitor of ABL1 kinase. The interaction of betulin and ABL1 was studied by molecular docking showing an interaction of the inhibitor with the ATP binding pocket. Altogether, these data demonstrate that betulin is a multi-target inhibitor of protein kinases, an activity that can contribute to the anticancer properties of the natural compound and notably for treatment of leukemia.

scholarly journals The selectivity of protein kinase inhibitors: a further update

2007 ◽  
Vol 408 (3) ◽  
pp. 297-315 ◽  
Author(s):  
Jenny Bain ◽  
Lorna Plater ◽  
Matt Elliott ◽  
Natalia Shpiro ◽  
C. James Hastie ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Specific Inhibitor ◽  
Protein Kinase Inhibitors ◽  
Mitogen Activated Protein Kinase ◽  
Casein Kinase 1

The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70–80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)–raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.

scholarly journals Identification of the glycogenic compound 5-iodotubercidin as a general protein kinase inhibitor

1994 ◽  
Vol 299 (1) ◽  
pp. 123-128 ◽  
Author(s):  
D Massillon ◽  
W Stalmans ◽  
G van de Werve ◽  
M Bollen
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Biological Effects ◽  
Glycogen Synthesis ◽  
Specific Protein ◽  
Liver Cells ◽  
Protein Kinase Inhibitor ◽  
Casein Kinase 1

Addition of micromolar concentrations of the adenosine derivative 5-iodotubercidin (Itu) initiates glycogen synthesis in isolated hepatocytes by causing inactivation of phosphorylase and activation of glycogen synthase [Flückiger-Isler and Walter (1993) Biochem. J. 292, 85-91]. We report here that Itu also antagonizes the effects of saturating concentrations of glucagon and vasopressin on these enzymes. The Itu-induced activation of glycogen synthase could not be explained by the removal of phosphorylase a (a potent inhibitor of the glycogen-associated synthase phosphatase). When tested on purified enzymes, Itu did not affect the activities of the major Ser/Thr-specific protein phosphatases (PP-1, PP-2A, PP-2B and PP-2C), but it inhibited various Ser/Thr-specific protein kinases as well as the tyrosine kinase activity of the insulin receptor (IC50 between 0.4 and 28 microM at 10-15 microM ATP). Tubercidin, which did not affect glycogen synthase or phosphorylase in liver cells, was 300 times less potent as a protein kinase inhibitor. Kinetic analysis of the inhibition of casein kinase-1 and protein kinase A showed that Itu acts as a competitive inhibitor with respect to ATP, and as a mixed-type inhibitor with respect to the protein substrate. We propose that Itu inactivates phosphorylase and activates glycogen synthase by inhibiting phosphorylase kinase and various glycogen synthase kinases. Consistent with the broad specificity of Itu in vitro, this compound decreased the phosphorylation level of numerous phosphopolypeptides in intact liver cells. Our data suggest that at least some of the biological effects of Itu can be explained by an inhibition of protein kinases.

scholarly journals Protein Tyrosine Kinases: Their Roles and Their Targeting in Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 184
Author(s):  
Kalpana K. Bhanumathy ◽  
Amrutha Balagopal ◽  
Frederick S. Vizeacoumar ◽  
Franco J. Vizeacoumar ◽  
Andrew Freywald ◽  
...  
Keyword(s):  
Growth Factor ◽  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinases ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Tyrosine Protein Kinase ◽  
Mesenchymal Epithelial Transition Factor ◽  
The Impact

Protein kinases constitute a large group of enzymes catalysing protein phosphorylation and controlling multiple signalling events. The human protein kinase superfamily consists of 518 members and represents a complicated system with intricate internal and external interactions. Protein kinases are classified into two main families based on the ability to phosphorylate either tyrosine or serine and threonine residues. Among the 90 tyrosine kinase genes, 58 are receptor types classified into 20 groups and 32 are of the nonreceptor types distributed into 10 groups. Tyrosine kinases execute their biological functions by controlling a variety of cellular responses, such as cell division, metabolism, migration, cell–cell and cell matrix adhesion, cell survival and apoptosis. Over the last 30 years, a major focus of research has been directed towards cancer-associated tyrosine kinases owing to their critical contributions to the development and aggressiveness of human malignancies through the pathological effects on cell behaviour. Leukaemia represents a heterogeneous group of haematological malignancies, characterised by an uncontrolled proliferation of undifferentiated hematopoietic cells or leukaemia blasts, mostly derived from bone marrow. They are usually classified as chronic or acute, depending on the rates of their progression, as well as myeloid or lymphoblastic, according to the type of blood cells involved. Overall, these malignancies are relatively common amongst both children and adults. In malignant haematopoiesis, multiple tyrosine kinases of both receptor and nonreceptor types, including AXL receptor tyrosine kinase (AXL), Discoidin domain receptor 1 (DDR1), Vascular endothelial growth factor receptor (VEGFR), Fibroblast growth factor receptor (FGFR), Mesenchymal–epithelial transition factor (MET), proto-oncogene c-Src (SRC), Spleen tyrosine kinase (SYK) and pro-oncogenic Abelson tyrosine-protein kinase 1 (ABL1) mutants, are implicated in the pathogenesis and drug resistance of practically all types of leukaemia. The role of ABL1 kinase mutants and their therapeutic inhibitors have been extensively analysed in scientific literature, and therefore, in this review, we provide insights into the impact and mechanism of action of other tyrosine kinases involved in the development and progression of human leukaemia and discuss the currently available and emerging treatment options based on targeting these molecules.

scholarly journals Multiple mechanisms for the phosphorylation of C-terminal regulatory sites in rabbit muscle glycogen synthase expressed in COS cells

1996 ◽  
Vol 313 (1) ◽  
pp. 45-50 ◽  
Author(s):  
Alexander V. SKURAT ◽  
Peter J. ROACH
Keyword(s):  
Protein Kinase ◽  
Protein Kinases ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Rabbit Muscle ◽  
Cos Cells ◽  
Additional Mutation ◽  
Regulatory Sites

Glycogen synthase can be inactivated by sequential phosphorylation at the C-terminal residues Ser652 (site 4), Ser648 (site 3c), Ser644 (site 3b) and Ser640 (site 3a) catalysed by glycogen synthase kinase-3. In vitro, glycogen synthase kinase-3 action requires that glycogen synthase has first been phosphorylated at Ser656 (site 5) by casein kinase II. Recently we demonstrated that inactivation is linked only to phosphorylation at site 3a and site 3b, and that, in COS cells, modification of these sites can occur by alternative mechanisms independent of any C-terminal phosphorylations [Skurat and Roach (1995) J. Biol. Chem. 270, 12491-12497]. To address these mechanisms multiple Ser → Ala mutations were introduced in glycogen synthase such that only site 3a or site 3b remained intact. Additional mutation of Arg637 → Gln eliminated phosphorylation of site 3a, indicating that Arg637 may be important for recognition of site 3a by its corresponding protein kinase(s). Similarly, additional mutation of Pro645 → Ala eliminated phosphorylation of site 3b, indicating a possible involvement of ‘proline-directed’ protein kinase(s). Mutation of Arg637 alone did not activate glycogen synthase as expected from the loss of phosphorylation at site 3a. Rather, mutation of both Arg637 and the Ser → Ala substitution at site 3b was required for substantial activation. The results suggest that sites 3a and 3b can be phosphorylated independently of one another by distinct protein kinases. However, phosphorylation of site 3b can potentiate phosphorylation of site 3a, by an enzyme such as glycogen synthase kinase-3.

scholarly journals Effects of Sunitinib and Other Kinase Inhibitors on Cells Harboring a PDGFRB Mutation Associated with Infantile Myofibromatosis

2018 ◽  
Vol 19 (9) ◽  
pp. 2599 ◽  
Author(s):  
Martin Sramek ◽  
Jakub Neradil ◽  
Petra Macigova ◽  
Peter Mudry ◽  
Kristyna Polaskova ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Cell Line ◽  
Tumor Cells ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Tumor Cell Line ◽  
Protein Kinase Inhibitors ◽  
Infantile Myofibromatosis ◽  
Pdgfr Beta

Infantile myofibromatosis represents one of the most common proliferative fibrous tumors of infancy and childhood. More effective treatment is needed for drug-resistant patients, and targeted therapy using specific protein kinase inhibitors could be a promising strategy. To date, several studies have confirmed a connection between the p.R561C mutation in gene encoding platelet-derived growth factor receptor beta (PDGFR-beta) and the development of infantile myofibromatosis. This study aimed to analyze the phosphorylation of important kinases in the NSTS-47 cell line derived from a tumor of a boy with infantile myofibromatosis who harbored the p.R561C mutation in PDGFR-beta. The second aim of this study was to investigate the effects of selected protein kinase inhibitors on cell signaling and the proliferative activity of NSTS-47 cells. We confirmed that this tumor cell line showed very high phosphorylation levels of PDGFR-beta, extracellular signal-regulated kinases (ERK) 1/2 and several other protein kinases. We also observed that PDGFR-beta phosphorylation in tumor cells is reduced by the receptor tyrosine kinase inhibitor sunitinib. In contrast, MAPK/ERK kinases (MEK) 1/2 and ERK1/2 kinases remained constitutively phosphorylated after treatment with sunitinib and other relevant protein kinase inhibitors. Our study showed that sunitinib is a very promising agent that affects the proliferation of tumor cells with a p.R561C mutation in PDGFR-beta.

scholarly journals Chronic Myeloid Leukemia in a Patient Receiving Tofacitinib: A Case Report and Literature Review

2019 ◽  
Vol 2019 ◽  
pp. 1-4
Author(s):  
Georgio Medawar ◽  
Joseph Chahrouri ◽  
Rabih Said
Keyword(s):  
Rheumatoid Arthritis ◽  
Case Report ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Myelogenous Leukemia ◽  
Janus Kinase Inhibitor ◽  
Case Presentation ◽  
Rheumatologic Diseases ◽  
Refractory Rheumatoid Arthritis

Background. Tofacitinib is a new oral Janus kinase inhibitor that has shown promising clinical benefit in various rheumatologic diseases. However, many concerns related to the development of malignancies have been reported with its use. Case Presentation. A 43-year-old female patient received tofacitinib for refractory rheumatoid arthritis (RA). Two years after 5 mg bid daily dosing, the patient developed chronic myelogenous leukemia (CML), for which she received imatinib and tofacitinib was discontinued. She then remained in remission for rheumatoid arthritis and within the expected milestone outcome for her CML. Conclusion. This is the first reported case of CML after the use of tofacitinib. This event is of particular interest knowing the possible benefits tofacitinib carries in the treatment of CML demonstrated in a few studies.

scholarly journals Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules

2019 ◽  
Vol 295 (3) ◽  
pp. 673-689 ◽  
Author(s):  
Friederike Hans ◽  
Hanna Glasebach ◽  
Philipp J. Kahle
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Osmotic Shock ◽  
Protein Kinase R ◽  
Extracellular Signal ◽  
Rapid Dissolution ◽  
The Central Nervous System

Insoluble, hyperubiquitylated TAR DNA-binding protein of 43 kDa (TDP-43) in the central nervous system characterizes frontotemporal dementia and ALS in many individuals with these neurodegenerative diseases. The causes for neuropathological TDP-43 aggregation are unknown, but it has been suggested that stress granule (SG) formation is important in this process. Indeed, in human embryonic kidney HEK293E cells, various SG-forming conditions induced very strong TDP-43 ubiquitylation, insolubility, and reduced splicing activity. Osmotic stress–induced SG formation and TDP-43 ubiquitylation occurred rapidly and coincided with colocalization of TDP-43 and SG markers. Washout experiments confirmed the rapid dissolution of SGs, accompanied by normalization of TDP-43 ubiquitylation and solubility. Surprisingly, interference with the SG process using a protein kinase R–like endoplasmic reticulum kinase inhibitor (GSK2606414) or the translation blocker emetine did not prevent TDP-43 ubiquitylation and insolubility. Thus, parallel pathways may lead to pathological TDP-43 modifications independent of SG formation. Using a panel of kinase inhibitors targeting signaling pathways of the osmotic shock inducer sorbitol, we could largely rule out the stress-activated and extracellular signal–regulated protein kinase modules and glycogen synthase kinase 3β. For arsenite, but not for sorbitol, quenching oxidative stress with N-acetylcysteine did suppress both SG formation and TDP-43 ubiquitylation and insolubility. Thus, sodium arsenite appears to promote SG formation and TDP-43 modifications via oxidative stress, but sorbitol stimulates TDP-43 ubiquitylation and insolubility via a novel pathway(s) independent of SG formation. In conclusion, pathological TDP-43 modifications can be mediated via multiple distinct pathways for which SGs are not essential.

scholarly journals Potential Role for Protein Kinases in Regulation of Bidirectional Endoplasmic Reticulum-to-Golgi Transport Revealed by Protein Kinase Inhibitor H89

2000 ◽  
Vol 11 (8) ◽  
pp. 2577-2590 ◽  
Author(s):  
Tina H. Lee ◽  
Adam D. Linstedt
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Kinase ◽  
Protein Kinase A ◽  
Protein Kinases ◽  
Potential Role ◽  
Kinase Inhibitor ◽  
Transport Processes ◽  
Protein Kinase Inhibitors ◽  
Er Export ◽  
Kinase A

Recent evidence suggests a regulatory connection between cell volume, endoplasmic reticulum (ER) export, and stimulated Golgi-to-ER transport. To investigate the potential role of protein kinases we tested a panel of protein kinase inhibitors for their effect on these steps. One inhibitor, H89, an isoquinolinesulfonamide that is commonly used as a selective protein kinase A inhibitor, blocked both ER export and hypo-osmotic-, brefeldin A-, or nocodazole-induced Golgi-to-ER transport. In contrast, H89 did not block the constitutive ER Golgi-intermediate compartment (ERGIC)-to-ER and Golgi-to-ER traffic that underlies redistribution of ERGIC and Golgi proteins into the ER after ER export arrest. Surprisingly, other protein kinase A inhibitors, KT5720 and H8, as well as a set of protein kinase C inhibitors, had no effect on these transport processes. To test whether H89 might act at the level of either the coatomer protein (COP)I or the COPII coat protein complex we examined the localization of βCOP and Sec13 in H89-treated cells. H89 treatment led to a rapid loss of Sec13-labeled ER export sites but βCOP localization to the Golgi was unaffected. To further investigate the effect of H89 on COPII we developed a COPII recruitment assay with permeabilized cells and found that H89 potently inhibited binding of exogenous Sec13 to ER export sites. This block occurred in the presence of guanosine-5′-O-(3-thio)triphosphate, suggesting that Sec13 recruitment is inhibited at a step independent of the activation of the GTPase Sar1. These results identify a requirement for an H89-sensitive factor(s), potentially a novel protein kinase, in recruitment of COPII to ER export sites, as well as in stimulated but not constitutive Golgi-to-ER transport.

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