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- Volume 30, Issue 13, 2023
Current Medicinal Chemistry - Volume 30, Issue 13, 2023
Volume 30, Issue 13, 2023
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Role of Tyrosine Kinases and their Inhibitors in Cancer Therapy: A Comprehensive Review
Authors: Vanktesh Kumar, Navjot Kaur, Sanjeev Sahu, Vikas Sharma, Deepak Kumar, Ajit Sharma and Pankaj WadhwaBackground: Cancer has been recognized as one of the non-communicable diseases with an increasing number of new cases, higher morbidity, and higher mortality rates at the global level. Thus, there is non-stop search for novel targets and small molecules to improve the chemotherapeutic outcomes concerning potency, selectivity, efficiency, affinity, ADMET, etc. Among anticancer therapeutic targets, tyrosine kinase has been documented well and approved as an important target with the development of various clinically used drugs. There are several structurally diverse small molecules in different preclinical and clinical stages of development that act by affecting tyrosine kinases in cancerous cells. Here, we have summarized different potent molecules acting against tyrosine kinases that can be considered as anticancer agents. Objective: The current review focused on structural aspects of different chemical agents for inhibition of tyrosine kinases as anticancer agents. Methods: The present study provides a summarized review of published information on tyrosine kinase inhibitors, their binding pattern, potencies, and structure-activity relationships. The review also highlighted the structural aspects of the interaction between inhibitors and amino acid residues of tyrosine kinases. Moreover, it also provided a summary of different types of cancers and the currently available options for treatment. Results: Several studies are being conducted for the inhibition of different tyrosine kinases using small molecules for the treatment of cancer. Tyrosine kinases have been reported involving in routine cellular functions, growth, and division of cells through different pathways which depend on phosphorylation. The overexpression and uncontrolled activity of tyrosine kinases have been identified as an important feature of cancerous cells. Thus, various small molecules have been reported which inhibit tyrosine kinases to block the growth and division of cancer cells. Here, more than 30 highly potent inhibitors of tyrosine kinases are summarised, which consist of pyrimidine, pyrazole, triazine, quinazoline, quinoline, pyrazine, chromene, etc. rings as a basic skeleton with different substituents. Conclusion: Inhibition of tyrosine kinases by different small molecules is an approved strategy for the development of novel anticancer agents. Several published reports have mentioned the characteristics of the different binding sites and crucial residues in tyrosine kinases for the design of novel molecular inhibitors. However, selectivity is an important criterion for the development of chemotherapeutic agents due to the existence of approximately 30 families of tyrosine kinases.
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Can Nanomedicinal Approaches Provide an Edge to the Efficacy of Tyrosine Kinase Inhibitors?
Authors: Sunaina Indermun, Pradeep Kumar, Mershen Govender and Yahya E. ChoonaraTyrosine kinase inhibitors (TKIs) are effective drug molecules for the treatment of various cancers. Nanomedicinal interventions and approaches may not only provide carrying capacities for TKIs but also potentially target tumor-specific environments and even cellular compartments. Nano-inspired drug delivery systems may hence enhance the efficacy of the drugs through enhanced tumour-availability resulting in greater efficacy and decreased side effects. A variety of nanosystems have been developed for the delivery of TKIs for the enhanced treatment of cancers, each with their own preparation methods and physicochemical properties. This review will therefore discuss the applicability of nano-interventions towards combination therapies, dose reduction, and greater potential treatment outcomes. The individual nanosystems have been highlighted with emphasis on the developed systems and their efficacy against various cancer cell lines and models.
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Kinase Inhibitors Involved in the Regulation of Autophagy: Molecular Concepts and Clinical Implications
All cells and intracellular components are remodeled and recycled in order to replace the old and damaged cells. Autophagy is a process by which damaged, and unwanted cells are degraded in the lysosomes. There are three different types of autophagy: macroautophagy, microautophagy, and chaperone-mediated autophagy. Autophagy has an effect on adaptive and innate immunity, suppression of any tumour, and the elimination of various microbial pathogens. The process of autophagy has both positive and negative effects, and this pertains to any specific disease or its stage of progression. Autophagy involves various processes which are controlled by various signaling pathways, such as Jun N-terminal kinase, GSK3, ERK1, Leucine-rich repeat kinase 2, and PTEN-induced putative kinase 1 and parkin RBR E3. Protein kinases are also important for the regulation of autophagy as they regulate the process of autophagy either by activation or inhibition. The present review discusses the kinase catalyzed phosphorylated reactions, the kinase inhibitors, types of protein kinase inhibitors and their binding properties to protein kinase domains, the structures of active and inactive kinases, and the hydrophobic spine structures in active and inactive protein kinase domains. The intervention of autophagy by targeting specific kinases may form the mainstay of treatment of many diseases and lead the road to future drug discovery.
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Recent Trends in Rationally Designed Molecules as Kinase Inhibitors
Protein kinases modulate the structure and function of proteins by adding phosphate groups to threonine, tyrosine, and serine residues. The phosphorylation process mediated by the kinases regulates several physiological processes, while their overexpression results in the development of chronic diseases, including cancer. Targeting of receptor tyrosine kinase pathways results in the inhibition of angiogenesis and cell proliferation that validates kinases as a key target in the management of aggressive cancers. As such, the identification of protein kinase inhibitors revolutionized the contemporary anticancer therapy by inducing a paradigm shift in the management of disease pathogenesis. Contemporary drug design programs focus on a broad range of kinase targets for the development of novel pharmacophores to manage the overexpression of kinases and their pathophysiology in cancer pathogenesis. In this review, we present the emerging trends in the development of rationally designed molecular inhibitors of kinases over the last five years (2016-2021) and their incipient role in the development of impending anticancer pharmaceuticals.
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Stable Gastric Pentadecapeptide BPC 157: Prompt Particular Activation of Collateral Pathways
Authors: Predrag Sikiric, Slaven Gojkovic, Mario Knezevic, Marijan Tepes, Sanja Strbe, Jaksa Vukojevic, Antonija Duzel, Tamara Kralj, Ivan Krezic, Helena Zizek, Katarina Oroz, Hrvoje Vranes, Ivan M. Smoday, Luka Kalogjera, Josipa Vlainic, Antonio Kokot, Ivana Jurjevic, Alenka Boban Blagaic, Anita Skrtic and Sven Seiwerth
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Volumes & issues
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Volume 31 (2024)
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Volume 30 (2023)
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Volume 29 (2022)
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Volume 28 (2021)
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Volume 27 (2020)
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Volume 26 (2019)
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Volume 25 (2018)
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Volume 24 (2017)
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Volume 23 (2016)
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Volume 22 (2015)
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Volume 21 (2014)
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Volume 20 (2013)
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Volume 19 (2012)
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Volume 18 (2011)
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Volume 17 (2010)
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Volume 16 (2009)
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Volume 15 (2008)
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Volume 14 (2007)
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Volume 13 (2006)
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Volume 12 (2005)
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Volume 11 (2004)
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Volume 10 (2003)
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Volume 9 (2002)
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Volume 8 (2001)
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Volume 7 (2000)