Synthesis and Biological Evaluations of 3-Substituted Indolin-2-ones:  A Novel Class of Tyrosine Kinase Inhibitors That Exhibit Selectivity toward Particular Receptor Tyrosine Kinases

Abstract Background Receptor tyrosine kinases (RTKs) are signaling enzymes responsible for the transfer of Adenosine triphosphate (ATP) γ-phosphate to the tyrosine residues substrates. RTKs demonstrate essential roles in cellular growth, metabolism, differentiation, and motility. Anomalous expression of RTK customarily leads to cell growth dysfunction, which is connected to tumor takeover, angiogenesis, and metastasis. Understanding the structure, mechanisms of adaptive and acquired resistance, optimizing inhibition of RTKs, and eradicating cum minimizing the havocs of quiescence cancer cells is paramount. MainText Tyrosine kinase inhibitors (TKIs) vie with RTKs ATP-binding site for ATP and hitherto reduce tyrosine kinase phosphorylation, thus hampering the growth of cancer cells. TKIs can either be monoclonal antibodies that compete for the receptor’s extracellular domain or small molecules that inhibit the tyrosine kinase domain and prevent conformational changes that activate RTKs. Progression of cancer is related to aberrant activation of RTKs due to due to mutation, excessive expression, or autocrine stimulation. Conclusions Understanding the modes of inhibition and structures of RTKs is germane to the design of novel and potent TKIs. This review shed light on the structures of tyrosine kinases, receptor tyrosine kinases, tyrosine kinase inhibitors, minimizing imatinib associated toxicities, optimization of tyrosine kinase inhibition in curtailing quiescence in cancer cells and the prospects of receptor tyrosine kinase based treatments.

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

Indian Journal of Pharmaceutical and Biological Research ◽

10.30750/ijpbr.3.2.10 ◽

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.

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Combating Acquired Resistance to Tyrosine Kinase Inhibitors in Lung Cancer

American Society of Clinical Oncology Educational Book ◽

10.14694/edbook_am.2015.35.e165 ◽

2015 ◽

pp. e165-e173 ◽

Cited By ~ 8

Author(s):

Christine M. Lovly

Keyword(s):

Lung Cancer ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Acquired Resistance ◽

Initial Response ◽

In Vitro Models ◽

Tumor Biopsy

The prospective identification and therapeutic targeting of oncogenic tyrosine kinases with tyrosine kinase inhibitors (TKIs) has revolutionized the treatment for patients with non–small cell lung cancer (NSCLC). TKI therapy frequently induces dramatic clinical responses in molecularly defined cohorts of patients with lung cancer, paving the way for the implementation of precision medicine. Unfortunately, acquired resistance, defined as tumor progression after initial response, seems to be an inevitable consequence of this treatment approach. This brief review will provide an overview of the complex and heterogeneous problem of acquired resistance to TKI therapy in NSCLC, with a focus on EGFR-mutant and ALK-rearranged NSCLC. In vitro models of TKI resistance and analysis of tumor biopsy samples at the time of disease progression have generated breakthroughs in our understanding of the spectrum of mechanisms by which a tumor can thwart TKI therapy and have provided an important rationale for the development of novel approaches to delay or overcome resistance. Numerous ongoing clinical trials implement strategies, including novel, more potent TKIs and rational combinations of targeted therapies, some of which have already proven effective in surmounting therapeutic resistance.

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Tyrosine kinases in etiopathogenesis and therapy of malignant diseases: c-kit activating mutations

Medicinski pregled ◽

10.2298/mpns1006380s ◽

2010 ◽

Vol 63 (5-6) ◽

pp. 380-386

Author(s):

Karmen Stankov ◽

Gordana Bogdanovic ◽

Stevan Popovic

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Tyrosine Kinases ◽

Malignant Disease ◽

Therapeutic Response ◽

Kinase Inhibitors ◽

New Technologies ◽

Cancer Therapeutics ◽

Activating Mutations ◽

Gene Expression Levels

Introduction. In the last 15 years, the introduction of molecular biology methods and techniques for identifying mutations and measuring gene expression levels of mutated genes since recently, have enabled precise molecular diagnostics, classification and assessment of prognosis and therapeutic response of malignant disease to specific therapies. The increased knowledge of the cancer genome and the introduction of multiple new technologies in cancer research have significantly improved the drug discovery process, leading to key success in targeted cancer therapeutics, including tyrosine kinase inhibitors. Tyrosine kinase inhibitors are the molecular targeted neoadjuvant and adjuvant therapy of various malignancies. Many more results which are expected from ongoing trials are necessary to specify the appropriate dosages, stages at which to start the treatment, and which therapeutic combinations to apply.

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Attenuation of endothelin-1-induced calcium response by tyrosine kinase inhibitors in vascular smooth muscle cells

AJP Cell Physiology ◽

10.1152/ajpcell.1996.270.6.c1825 ◽

1996 ◽

Vol 270 (6) ◽

pp. C1825-C1833 ◽

Cited By ~ 23

Author(s):

C. Y. Liu ◽

M. Sturek

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Tyrosine Kinase ◽

Smooth Muscle Cells ◽

Tyrosine Kinase Inhibitors ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Muscle Cells ◽

Endothelin 1 ◽

Fura 2

Although tyrosine kinases play an important role in cell growth and have been implicated in regulation of smooth muscle contraction, their role in agonist-induced myoplasmic Ca2+ responses is unclear. We examined effects of the tyrosine kinase inhibitors genistein and methyl 2,5-dihydroxycinnamate (MDHC) on the endothelin-1 (ET-1)-induced Ca2+ response and determined underlying mechanisms for the effects. Freshly isolated smooth muscle cells from porcine coronary arteries were loaded with fura 2 ester, and myoplasmic free Ca2+ (Ca2+ (m)) concentration was estimated with fura 2 microfluorometry. Both genistein and MDHC inhibited the initial transient Cam2+ response to ET by 54 and 81%, respectively (P < 0.05), in the presence of extracellular Ca2+. Genistein also significantly delayed the Cam2+ response, with the latent period from ET-1 application to the beginning of the Cam2+ response being increased from 1.08 +/- 0.17 to 2.65 +/- 0.52 min (P < 0.05). In the absence of extracellular Ca2+, genistein inhibited the ET-1-induced Cam2+ response by 93% (P < 0.05). The Cam2+ responses to caffeine (5 mM) or inositol trisphosphate (IP3) applied intracellularly via a patch-clamp pipette were not affected by genistein. Both genistein and MDHC also abolished the sustained Cam2+ response to ET-1. However, the Cam2+ response to depolarization by 80 mM K+ was not inhibited by MDHC and only inhibited 22% by genistein (P < 0.05). These results indicate that 1) activation of tyrosine kinases is an important regulatory mechanism for the ET-1-induced Cam2+ response in vascular smooth muscle and 2) tyrosine kinases mediate ET-1-induced Ca2+ release with no direct effect on IP3-mediated Ca2+ release. Thus ET-1-mediated signaling upstream of IP3 interaction with the Ca2+ stores is regulated by tyrosine kinases.

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

American Journal of PharmacoGenomics ◽

10.2165/00129785-200505020-00003 ◽

2005 ◽

Vol 5 (2) ◽

pp. 101-112 ◽

Cited By ~ 10

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

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The Use of Inhibitors of Tyrosine Kinase in Paediatric Haemato-Oncology—When and Why?

International Journal of Molecular Sciences ◽

10.3390/ijms222112089 ◽

2021 ◽

Vol 22 (21) ◽

pp. 12089

Author(s):

Agnieszka Kaczmarska ◽

Patrycja Śliwa ◽

Monika Lejman ◽

Joanna Zawitkowska

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Target Therapy ◽

Critical Role ◽

Current Data ◽

Childhood Cancers ◽

Therapeutic Approaches ◽

New Therapeutic Approaches

The fundamental pathophysiology of malignancies is dysregulation of the signalling pathways. Protein tyrosine kinases (PTKs) are among the enzymes which, if mutated, play a critical role in carcinogenesis. The best-studied rearrangement, which enhances PTK activity and causes atypical proliferation, is BCR-ABL1. Abnormal expression of PTKs has proven to play a significant role in the development of various malignancies, such as chronic myelogenous leukaemia, brain tumours, neuroblastoma, and gastrointestinal stromal tumours. The use of tyrosine kinase inhibitors (TKIs) is an outstanding example of successful target therapy. TKIs have been effectively applied in the adult oncology setting, but there is a need to establish TKIs’ importance in paediatric patients. Many years of research have allowed a significant improvement in the outcome of childhood cancers. However, there are still groups of patients who have a poor prognosis, where the intensification of chemotherapy could even cause death. TKIs are designed to target specific PTKs, which lead to the limitation of severe adverse effects and increase overall survival. These advances will hopefully allow new therapeutic approaches in paediatric haemato-oncology to emerge. In this review, we present an analysis of the current data on tyrosine kinase inhibitors in childhood cancers.

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Tyrosine kinase inhibitors and modifications of thyroid function tests: a review

Acta Endocrinologica ◽

10.1530/eje-08-0648 ◽

2009 ◽

Vol 160 (3) ◽

pp. 331-336 ◽

Cited By ~ 59

Author(s):

Frédéric Illouz ◽

Sandrine Laboureau-Soares ◽

Séverine Dubois ◽

Vincent Rohmer ◽

Patrice Rodien

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Thyroid Function ◽

Tyrosine Kinases ◽

Kinase Inhibitors ◽

Thyroid Function Tests ◽

Hormone Regulation ◽

Clinical Observations ◽

Function Tests ◽

First Case

Tyrosine kinase inhibitors (TKI) belong to new molecular multi-targeted therapies that are approved for the treatment of haematological and solid tumours. They interact with a large variety of protein tyrosine kinases involved in oncogenesis. In 2005, the first case of hypothyroidism was described and since then, some data have been published and have confirmed that TKI can affect the thyroid function tests (TFT). This review analyses the present clinical and fundamental findings about the effects of TKI on the thyroid function. Various hypotheses have been proposed to explain the effect of TKI on the thyroid function but those are mainly based on clinical observations. Moreover, it appears that TKI could alter the thyroid hormone regulation by mechanisms that are specific to each molecule. The present propositions for the management of TKI-induced hypothyroidism suggest that we assess the TFT of the patients regularly before and during the treatment by TKI. Thus, a better approach of patients with TKI-induced hypothyroidism could improve their quality of life.

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