scholarly journals Identification of Potential Off-Targets of Chemotherapeutic Agent Sorafenib: A Molecular Docking Approach

2016 ◽  
Vol 51 ◽  
pp. 51-57
Author(s):  
Tammanna R. Sahrawat ◽  
Parul Chawla
Keyword(s):  
Molecular Docking ◽  
Growth Factor ◽  
Tyrosine Kinases ◽  
Chemotherapeutic Agent ◽  
Growth Factor Receptor ◽  
Tyrosine Kinase Receptor ◽  
Downstream Signaling ◽  
Docking Approach ◽  
Minimum Number ◽  
Surface Similarity

B-Raf is a multi- drug target serine/threonine protein kinase, involved in the transduction of mitogenic signals from the cell membrane to the nucleus. Mutated B-Raf causes overactive downstream signaling via MEK and ERK, leading to excessive cell proliferation and survival, independent of growth factors causing cancers such as Pancreatic carcinoma. A novel bi-aryl urea- Sorafenib, is a potent inhibitor of Raf-1 that has been approved for the treatment of a number of cancers including pancreatic cancer. The present investigation was designed to identify the potential off-targets of Sorafenib which could be responsible for its reported undesirable side effects. Molecular docking was used to test the efficacy of structural analogs of Sorafenib against B-Raf using FlexX and it was found that the analog with CID:10151557 had a high potency with minimum number of clashes, low lipophilic score and high match score, similar to Sorafenib. To identify the potential off-target/s of Sorafenib, macromolecular surface similarity detection software MEDIT SA MED-SuMo was used and the results obtained were validated through literature. The possible off-targets obtained belonged to the family of protein tyrosine kinases i.e. VEGFR-2, VEGFR-3, platelet-derived growth factor receptor beta, Flt-3, and c-KIT, each of which were docked with Sorafenib. Based on high docking scores and similarity with B-Raf for its binding site interacting residues, it was concluded that Vascular endothelial growth factor tyrosine kinase receptor (VEGFR) is a potential off-target of anti-cancer chemotherapeutic agent Sorafenib.

scholarly journals Validation of a Phosphoprotein Array Assay for Characterization of Human Tyrosine Kinase Receptor Downstream Signaling in Breast Cancer

2009 ◽  
Vol 55 (7) ◽  
pp. 1327-1336 ◽  
Author(s):  
Fadila Chergui ◽  
Anne-Sophie Chrétien ◽  
Sanae Bouali ◽  
Carole Ramacci ◽  
Marie Rouyer ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Western Blot ◽  
Growth Factor Receptor ◽  
Antibody Detection ◽  
Tyrosine Kinase Receptor ◽  
Downstream Signaling ◽  
Epidermal Growth

Abstract Background: Human epidermal growth factor receptor (HER) downstream signaling kinases have important effects on tumor response to anti-HER monoclonal antibodies and tyrosine kinase inhibitors. We validated an assay that uses phosphoprotein arrays for measurement of HER downstream signaling functionality in breast carcinomas. Methods: Using the Bio-Plex® phosphoprotein array (BPA), we performed multiplex immunoanalysis to investigate the expression of phosphorylated epidermal growth factor receptor and phosphorylated HER downstream signaling proteins (phosphorylated protein kinase B, phosphorylated glycogen synthase kinase −3β, phosphorylated P70 ribosomal protein S6 kinase, and phosphorylated extracellular signal regulated kinase 42/44) in 49 frozen specimens of ductal infiltrating breast carcinoma taken at diagnosis. BPA was cross-validated with Western blot analysis. Sample size, homogenicity, tumor content, protein extraction, and monoclonal antibody detection were in accordance with optimized standard operating procedures. Results: Linear regression showed significant quantitative correlations between BPA and Western blot, with regression coefficient values of 0.71–0.87 (P < 0.001). BPA intra- and interassay CVs were <17% and 15%, respectively. Compared to limits of detection established by using the mean + 3SD of 10 blanks, large variations of phosphoprotein expression, up to several hundred-fold, were observed among the 49 tumor specimens. Conclusions: Our results validate the use of the multiplex phosphoprotein array assay in human clinical tumor specimens. Further prospective evaluation is warranted to investigate the use of HER downstream signaling phosphoproteins as predictive and/or surrogate markers for clinical response to anti-HER targeted therapy. .

scholarly journals Receptor-Tyrosine-Kinase-Targeted Therapies for Head and Neck Cancer

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Lisa A. Elferink ◽  
Vicente A. Resto
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Cross Talk ◽  
Tyrosine Kinases ◽  
Cell Cancer ◽  
Growth Factor Receptor ◽  
Cell Loss ◽  
Specific Method ◽  
Downstream Signaling ◽  
Molecular Therapeutics

Molecular therapeutics for treating epidermal growth factor receptor-(EGFR-) expressing cancers are a specific method for treating cancers compared to general cell loss with standard cytotoxic therapeutics. However, the finding that resistance to such therapy is common in clinical trials now dampens the initial enthusiasm over this targeted treatment. Yet an improved molecular understanding of other receptor tyrosine kinases known to be active in cancer has revealed a rich network of cross-talk between receptor pathways with a key finding of common downstream signaling pathways. Such cross talk may represent a key mechanism for resistance to EGFR-directed therapy. Here we review the interplay between EGFR and Met and the type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinases, as well as their contribution to anti-EGFR therapeutic resistance in the context of squamous cell cancer of the head and neck, a tumor known to be primarily driven by EGFR-related oncogenic signals.

scholarly journals Status of Agents Targeting the HGF/c-Met Axis in Lung Cancer

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 280 ◽  
Author(s):  
Oshin Miranda ◽  
Mariya Farooqui ◽  
Jill Siegfried
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Past Research ◽  
Cell Types ◽  
Tyrosine Kinase Receptor ◽  
Mesenchymal Epithelial Transition Factor ◽  
Hepatocyte Growth

Hepatocyte growth factor (HGF) is the ligand for the tyrosine kinase receptor c-Met (Mesenchymal Epithelial Transition Factor also known as Hepatocyte Growth Factor Receptor, HGFR), a receptor with expression throughout epithelial and endothelial cell types. Activation of c-Met enhances cell proliferation, invasion, survival, angiogenesis, and motility. The c-Met pathway also stimulates tissue repair in normal cells. A body of past research shows that increased levels of HGF and/or overexpression of c-Met are associated with poor prognosis in several solid tumors, including lung cancer, as well as cancers of the head and neck, gastro-intestinal tract, breast, ovary and cervix. The HGF/c-Met signaling network is complex; both ligand-dependent and ligand-independent signaling occur. This article will provide an update on signaling through the HGF/c-Met axis, the mechanism of action of HGF/c-Met inhibitors, the lung cancer patient populations most likely to benefit, and possible mechanisms of resistance to these inhibitors. Although c-Met as a target in non-small cell lung cancer (NSCLC) showed promise based on preclinical data, clinical responses in NSCLC patients have been disappointing in the absence of MET mutation or MET gene amplification. New therapeutics that selectively target c-Met or HGF, or that target c-Met and a wider spectrum of interacting tyrosine kinases, will be discussed.

Targeting Small Molecule Tyrosine Kinases by Polyphenols: New Move Towards Anti-tumor Drug Discovery

2020 ◽  
Vol 17 (5) ◽  
pp. 585-615 ◽  
Author(s):  
Nikhil S. Sakle ◽  
Shweta A. More ◽  
Sachin A. Dhawale ◽  
Santosh N. Mokale
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Small Molecule ◽  
Anaplastic Lymphoma Kinase ◽  
Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Myelogenous Leukemia ◽  
Cell Functions ◽  
Anaplastic Lymphoma

Background: Cancer is a complex disease involving genetic and epigenetic alteration that allows cells to escape normal homeostasis. Kinases play a crucial role in signaling pathways that regulate cell functions. Deregulation of kinases leads to a variety of pathological changes, activating cancer cell proliferation and metastases. The molecular mechanism of cancer is complex and the dysregulation of tyrosine kinases like Anaplastic Lymphoma Kinase (ALK), Bcr-Abl (Fusion gene found in patient with Chronic Myelogenous Leukemia (CML), JAK (Janus Activated Kinase), Src Family Kinases (SFKs), ALK (Anaplastic lymphoma Kinase), c-MET (Mesenchymal- Epithelial Transition), EGFR (Epidermal Growth Factor receptor), PDGFR (Platelet-Derived Growth Factor Receptor), RET (Rearranged during Transfection) and VEGFR (Vascular Endothelial Growth Factor Receptor) plays major role in the process of carcinogenesis. Recently, kinase inhibitors have overcome many problems of traditional cancer chemotherapy as they effectively separate out normal, non-cancer cells as well as rapidly multiplying cancer cells. Methods: Electronic databases were searched to explore the small molecule tyrosine kinases by polyphenols with the help of docking study (Glide-7.6 program interfaced with Maestro-v11.3 of Schrödinger 2017) to show the binding energies of polyphenols inhibitor with different tyrosine kinases in order to differentiate between the targets. Results: From the literature survey, it was observed that the number of polyphenols derived from natural sources alters the expression and signaling cascade of tyrosine kinase in various tumor models. Therefore, the development of polyphenols as a tyrosine kinase inhibitor against targeted proteins is regarded as an upcoming trend for chemoprevention. Conclusion: In this review, we have discussed the role of polyphenols as chemoreceptive which will help in future for the development and discovery of novel semisynthetic anticancer agents coupled with polyphenols.

scholarly journals Molecular Engineering of Curcumin, an Active Constituent of Curcuma longa L. (Turmeric) of the Family Zingiberaceae with Improved Antiproliferative Activity

Plants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1559
Author(s):  
Amena Ali ◽  
Abuzer Ali ◽  
Abu Tahir ◽  
Md. Afroz Bakht ◽  
Salahuddin ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Molecular Docking ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Line ◽  
Antiproliferative Activity ◽  
Growth Factor Receptor ◽  
Molecular Engineering ◽  
Curcumin Analogs ◽  
Epidermal Growth

Cancer is the world’s second leading cause of death, accounting for nearly 10 million deaths and 19.3 million new cases in 2020. Curcumin analogs are gaining popularity as anticancer agents currently. We reported herein the isolation, molecular engineering, molecular docking, antiproliferative, and anti-epidermal growth factor receptor (anti-EGFR) activities of curcumin analogs. Three curcumin analogs were prepared and docked against the epidermal growth factor receptor (EGFR), revealing efficient binding. Antiproliferative activity against 60 NCI cancer cell lines was assessed using National Cancer Institute (NCI US) protocols. The compound 3b,c demonstrated promising antiproliferative activity in single dose (at 10 µM) as well as five dose (0.01, 0.10, 1.00, 10, and 100 µM). Compound 3c inhibited leukemia cancer panel better than other cancer panels with growth inhibition of 50% (GI50) values ranging from 1.48 to 2.73 µM, and the most promising inhibition with GI50 of 1.25 µM was observed against leukemia cell line SR, while the least inhibition was found against non-small lung cancer cell line NCI-H226 with GI50 value of 7.29 µM. Compounds 3b,c demonstrated superior antiproliferative activity than curcumin and gefitinib. In molecular docking, compound 3c had the most significant interaction with four H-bonds and three π–π stacking, and compound 3c was found to moderately inhibit EGFR. The curcumin analogs discovered in this study have the potential to accelerate the anticancer drug discovery program.

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 Structure-based design of some quinazoline derivatives as epidermal growth factor receptor inhibitors

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Muhammad Tukur Ibrahim ◽  
Adamu Uzairu ◽  
Gideon Adamu Shallangwa ◽  
Sani Uba
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Growth Factor Receptor ◽  
Pharmacokinetic Profile ◽  
Egfr Inhibitors ◽  
Tyrosine Kinase Receptor ◽  
Egfr Tyrosine Kinase ◽  
Epidermal Growth

Abstract Background The discovery of epidermal growth factor receptor (EGFR) inhibitors for the treatment of lung cancer, most especially non-small cell lung cancer (NSCLC), was one of the major challenges encountered by the medicinal chemist in the world. The treatment of EGFR tyrosine kinase to manage NSCLCs becomes an urgent therapeutic necessity. NSCLC was the foremost cause of cancer mortality worldwide. Therefore, there is a need to develop more EGFR inhibitors due to the development of drug resistance by the mutation. This research is aimed at designing new EGFR inhibitors using a structure-based design approach. Structure-based drug design comprises several steps such as protein structure retrieval and preparation, ligand library preparation, docking, and structural modification on the best hit compound to design new ones. Result Molecular docking virtual screening on fifty sets of quinazoline derivatives/epidermal growth factor receptor inhibitors against their target protein (EGFR tyrosine kinase receptor PDB entry: 3IKA) and pharmacokinetic profile predictions were performed to identify hit compounds with promising affinities toward their target and good pharmacokinetic profiles. The hit compounds identified were compound 6 with a binding affinity of − 9.3 kcal/mol, compounds 5 and 8, each with a binding affinity of − 9.1 kcal/mol, respectively. The three hit compounds bound to EGFR tyrosine kinase receptor via four different types of interactions which include conventional hydrogen bond, carbon-hydrogen bond, electrostatic, and hydrophobic interactions, respectively. The best hit (compound 6) among the 3 hit compounds was retained as a template and used to design sixteen new EGFR inhibitors. The sixteen newly designed compounds were also docked into the active site of EGFR tyrosine kinase receptor to study their mode of interactions with the receptor. The binding affinities of these newly designed compounds range from − 9.5 kcal/mol to − 10.2 kcal/mol. The pharmacokinetic profile predictions of these newly designed compounds were further examined and found to be orally bioavailable with good absorption, low toxicity level, and permeable properties. Conclusion The sixteen newly designed EGFR inhibitors were found to have better binding affinities than the template used in the designing process and afatinib the positive control (an FDA approved EGFR inhibitor). None of these designed compounds was found to violate more than the permissible limit set by RO5. More so, the newly designed compounds were found to have good synthetic accessibility which indicates that these newly designed compounds can be easily synthesized in the laboratory.

scholarly journals The Motile Breast Cancer Phenotype Roles of Proteoglycans/Glycosaminoglycans

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Dragana Nikitovic ◽  
Katerina Kouvidi ◽  
Kallirroi Voudouri ◽  
Aikaterini Berdiaki ◽  
Evgenia Karousou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Downstream Signaling ◽  
Insulin Growth Factor ◽  
Cancer Pathogenesis ◽  
Cellular Mediators ◽  
Epidermal Growth ◽  
Cancer Phenotype ◽  
Insulin Growth Factor Receptor

The consecutive stages of cancer growth and dissemination are obligatorily perpetrated through specific interactions of the tumor cells with their microenvironment. Importantly, cell-associated and tumor microenvironment glycosaminoglycans (GAGs)/proteoglycan (PG) content and distribution are markedly altered during tumor pathogenesis and progression. GAGs and PGs perform multiple functions in specific stages of the metastatic cascade due to their defined structure and ability to interact with both ligands and receptors regulating cancer pathogenesis. Thus, GAGs/PGs may modulate downstream signaling of key cellular mediators including insulin growth factor receptor (IGFR), epidermal growth factor receptor (EGFR), estrogen receptors (ERs), or Wnt members. In the present review we will focus on breast cancer motility in correlation with their GAG/PG content and critically discuss mechanisms involved. Furthermore, new approaches involving GAGs/PGs as potential prognostic/diagnostic markers or as therapeutic agents for cancer-related pathologies are being proposed.

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