Research progress in quinazoline derivatives as multi-target tyrosine kinase inhibitors

2018 ◽  
Vol 24 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Hao Jin ◽  
Hu-Guang Dan ◽  
Guo-Wu Rao
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Small Molecule ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Synthetic Methods ◽  
Research Progress ◽  
Quinazoline Derivatives ◽  
Antitumor Bioactivity

Abstract Receptor tyrosine kinases (RTKs), such as epidermal growth factor receptor (EGFR), are involved in multiple human tumors. Therefore, RTKs are attractive targets for various antitumor strategies. Two classes of tyrosine kinase antagonists were applied in the clinic for monoclonal antibodies and small-molecule tyrosine kinase inhibitors. A well-studied class of small-molecule inhibitors is represented by 4-anilinoquinazolines, exemplified by gefitinib and erlotinib as mono-targeted EGFR inhibitors, which were approved for the treatment of non-small-cell lung cancer. Mono-target drugs may result in drug resistance and the innovation of multi-target drugs has grown up to be an active field. Recent advances in research on antitumor bioactivity of 4-anilino(or phenoxy)quinazoline derivatives with multiple targets are reviewed in this paper. At the same time, synthetic methods of quinazolines were introduced from the point of building the ring skeleton and based on the types of reaction.

scholarly journals Tyrosine Kinase Inhibitors in the Combination Therapy of HER2 Positive Breast Cancer

2020 ◽  
Vol 19 ◽  
pp. 153303382096214
Author(s):  
Xue Yang ◽  
Dapeng Wu ◽  
Shengli Yuan
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) accounts for about 20% to 30% of all BC subtypes and is characterized by invasive disease and poor prognosis. With the emergence of anti-HER2 target drugs, HER2-positive BC patient outcomes have changed dramatically. However, treatment failure is mostly due to drug resistance and the special treatment needs of different subgroups. Small molecule tyrosine kinase inhibitors can inhibit multiple targets of the human epidermal growth factor receptor family and activate PI3K/AKT, MAPK, PLC γ, ERK1/2, JAK/STAT, and other pathways affecting the expression of MDM2, mTOR, p27, and other transcription factors. This can help regulate the differentiation, apoptosis, migration, growth, and adhesion of normal cells and reverse drug resistance to a certain extent. These inhibitors can cross the blood-brain barrier and be administered orally. They have a good synergistic effect with effective drugs such as trastuzumab, pertuzumab, t-dm1, and cyclin-dependent kinase 4 and 6 inhibitors. These advantages have resulted in small-molecule tyrosine kinase inhibitors attracting attention. The new small-molecule tyrosine kinase inhibitor was investigated in multi-target anti-HER2 therapy, showed a good effect in preclinical and clinical trials, and to some extent, improved the prognosis of HER2-positive BC patients. Its use could lead to a de-escalation of treatment in some patients, possibly preventing unnecessary procedures along with the associated side effects and costs.

Mechanisms of Clinical Resistance to Small Molecule Tyrosine Kinase Inhibitors Targeting Oncogenic Tyrosine Kinases

2005 ◽  
Vol 5 (2) ◽  
pp. 101-112 ◽  
Author(s):  
Heiko van der Kuip ◽  
Lara Wohlbold ◽  
Carsten Oetzel ◽  
Matthias Schwab ◽  
Walter E Aulitzky
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Small Molecule ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Clinical Resistance

scholarly journals Subcellular localization of several structurally different tyrosine kinase inhibitors

ADMET & DMPK ◽  
2018 ◽  
Vol 6 (3) ◽  
pp. 258-266 ◽  
Author(s):  
Richard Honeywell ◽  
Sarina Hitzerd ◽  
Ietje Kathmann ◽  
Godefridus Peters
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Similar Distribution ◽  
Lysosomal Accumulation ◽  
Vegfr Inhibitor ◽  
General Localization

Protein tyrosine kinases form an important target for a new class of anticancer drugs, the tyrosine kinase inhibitors (TKIs). Recently we demonstrated that sunitinib, an inhibitor of the membrane-associated vascular endothelial growth factor receptor (VEGFR), is trapped in lysosomes which isolates the drug from its intended target. Therefore we investigated whether this also holds for other TKIs, targeted against different protein kinases. For this purpose we used the ProteoExtractR kit, which enables a subcellular extraction separating cellular proteins into four distinct fractions covering the cytosol, membranes and membrane organelles (including lysosomes), nuclear proteins and the cytoskeleton. Since TKIs are 98-100 % protein bound we used this property to study their subcellular distribution and used Caco-2 cells as a model. As expected after 2 hours exposure sunitinib was trapped in cytosol (58 %) and organelles (42 % including lysosomes). Crizotinib, an inhibitor of ALK-EML4, showed a similar distribution. However, erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) showed a very low cellular accumulation and was limited to the organelle fraction. In contrast, the other EGFR inhibitor, gefitinib was predominantly located in the cytosolic (39 %) and membrane fraction (44 %). Sorafenib, another VEGFR inhibitor was predominantly located in the organelle fraction (85 %) and cytosol (15 %) after 2 hours, while after 24 hours distribution decreased (9.9 fold) with a slight shift. Dasatinib, an inhibitor of BCR-Abl was located only in the cytosol (100 %). In general localization after 24 hours was comparable, albeit several small changes were seen. In conclusion protein fractionation with the ProteoExtractR Subcellular Proteome Extraction kit demonstrated large differences in TKI levels in various cellular organelles, with a pattern in agreement with lysosomal accumulation of sunitinib.

scholarly journals Tyrosine Kinase Inhibitors in Adult Glioblastoma: An (Un)Closed Chapter?

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5799
Author(s):  
Paula Aldaz ◽  
Imanol Arozarena
Keyword(s):  
Clinical Trials ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Growth Factor Receptor ◽  
Medical Community ◽  
Molecular Events

Glioblastoma (GBM) is the most common and lethal form of malignant brain tumor. GBM patients normally undergo surgery plus adjuvant radiotherapy followed by chemotherapy. Numerous studies into the molecular events driving GBM highlight the central role played by the Epidermal Growth Factor Receptor (EGFR), as well as the Platelet-derived Growth Factor Receptors PDGFRA and PDGFRB in tumor initiation and progression. Despite strong preclinical evidence for the therapeutic potential of tyrosine kinase inhibitors (TKIs) that target EGFR, PDGFRs, and other tyrosine kinases, clinical trials performed during the last 20 years have not led to the desired therapeutic breakthrough for GBM patients. While clinical trials are still ongoing, in the medical community there is the perception of TKIs as a lost opportunity in the fight against GBM. In this article, we review the scientific rationale for the use of TKIs targeting glioma drivers. We critically analyze the potential causes for the failure of TKIs in the treatment of GBM, and we propose alternative approaches to the clinical evaluation of TKIs in GBM patients.

scholarly journals Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-small cell lung cancer

2015 ◽  
Vol 3 (02) ◽  
pp. 81-87
Author(s):  
Lawaly Maman Manzo ◽  
Moudirat Lawaly ◽  
Lui YU
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Receptor Tyrosine Kinases ◽  
Growth Factor Receptor ◽  
Endothelial Growth Factor ◽  
Receptor Tyrosine Kinase Inhibitors

Aberrant increased expression and activation of receptor tyrosine kinases occur frequently in human carcinomas. Several small molecules targeting receptor tyrosine kinases, which have crucial roles in the growth factor signaling that promote tumor progression in various malignancies, including non-small cell lung cancer (NSCLC), are currently in clinical development. Therapeutic strategies include inhibition of growth factor tyrosine kinase function. Drugs of this type include those that target the epidermal growth factor receptor tyrosine kinase, those that target vascular endothelial growth factor receptors tyrosine kinase and those that target anaplastic lymphoma receptor tyrosine kinase. In this review we first discuss the role of receptor tyrosine kinases in human malignancies, and focus on discussing the potential use of epidermal growth factor receptor tyrosine kinase inhibitors and the vascular endothelial growth factor receptors tyrosine kinase inhibitors in NSCLC. In addition, we discuss the contribution of growth factor receptor tyrosine kinase inhibitors to the clinically observed resistance, and toxicity.

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.

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