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Published in Valerio Voliani, Nanomaterials and Neoplasms, 2021
Eun-Kyung Lim, Taekhoon Kim, Soonmyung Paik, Seungjoo Haam, Yong-Min Huh, Kwangyeol Lee
Tyrosine kinases that are responsible for activation of signal transduction cascades can be inhibited by tyrosine kinase inhibitors. These are used as anticancer drugs by competing with ATP [211]. About 15%–20% of patients with early-stage breast cancer have tumors that overexpress or amplify HER2 genes, which is associated with increased proliferation of cancer cells and poor prognosis [390–394]. When HER2 binds to the ligands (preferably forming dimers), the HER2 pathway can initiate the mitogen-activated protein kinase pathway as well as the PI3K/Akt pathway, which in turn activates the nuclear factor kappa B pathway. When growth factors bind to their receptors on the cell surface, the receptors give a signal causing cell division. However, if growth factor receptor inhibitors bind to their receptors, the receptors no longer cause uncontrolled cell proliferation. Trastuzumab (Herceptin) is a HER2-specific mAb and the only approved HER2-targeted drug. Cells targeted with trastuzumab experience cell cycle arrest in the G phase; thus, cell proliferation is reduced by downregulation of HER2/neu [383, 384]. When cancer develops it requires generation of neovasculature for nutrient and oxygen supply. Trastuzumab suppresses angiogenesis, formation of new blood vessels, by both induction of antiangiogenic factors and repression of proangiogenic factors. Cetuximab (Erbitux), an EGFR inhibitor, binds to EGFR and inhibits uncontrolled growth of cancers with EGFR mutations [215, 216, 395–400].
N-Heterocycles
Published in Navjeet Kaur, Metals and Non-Metals, 2020
The arylboronic acid reacted well with pyridine ring in Suzuki-Miyaura cross-coupling reactions [116–119]. The products of pyridine-bearing reactants are transformed into pyrazolo-3,4-pyridines upon heating with NH2NH2·H2O in PhMe for 4 hours at 80 °C. As the members of this class of heterocyclic compounds are kinase inhibitors, they exhibit anti-cancer properties [120]. The pyrazolo-3,4-pyridines are formed in 88% yield when pyridine-containing reactants are treated with NH2NH2·H2O at 80 °C in PhMe for 4 hours. The Suzuki-Miyaura cross-coupling and cyclization step can be combined in a one-pot protocol, starting from bromopyridine, which is subjected to palladium-catalyzed cross-coupling with arylboronic acid and subsequently reacts with NH2NH2·H2O to produce pyrazolo-3,4-pyridine in 77% yield (Scheme 65–66) [84b, 121].
Resistance Mechanisms of Tumor Cells
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Since chromosomal translocations are the hallmark of nearly all hematological tumors (a few leukemias are associated with either hyperdiploid of hypodiploid genomes), very few secondary mutations were usually identified in whole genome sequencing projects. Secondary aberrations could be diagnosed only in subpopulations, indicating that they are not necessarily driving tumor development rather than prepare the ground for selection processes (Dobbins et al., 2013; Martelli et al., 2013; Anderson et al., 2015; Bodini et al., 2015; Lindqvist et al., 2015; Stieglitz et al., 2015; Ding et al., 2017; Bolouri et al., 2018). Based on our current knowledge, the chimeric fusion genes are sufficient to cause the onset and maintenance of the different disease types (AML, ALL). Thus, these chimeric fusion genes are highly malignant when expressed in the appropriate hematopoietic (stem- or precursor cell) compartment. These fusion genes change either the epigenetic set-up and/or transcriptional profiles (e.g., MLL-r leukemias), or convert existing “physiological” into “oncogenic signaling pathways” (e.g., BCR-ABL). The latter cases can be quite successfully treated by the available TKIs (tyrosine kinase inhibitors such as Imatinib) and KIs (kinase inhibitors). The success of these novel therapies for certain patient groups has led to the term “personalized medicine,” which is based on the rational treatment of patient based on their diagnosed gene mutations (or present ‘fusion gene’).
An insight on the different synthetic routes for the facile synthesis of O/S-donor carbamide/thiocarbamide analogs and their miscellaneous pharmacodynamic applications
Published in Journal of Sulfur Chemistry, 2023
Faiza Asghar, Bushra Shakoor, Babar Murtaza, Ian S. Butler
Protein kinase inhibitors block the action of protein kinases that are being involved in phosphorylation (addition of phosphate group to a protein), which in turn became the protein effective or ineffective and, therefore, affects its level of activity and function. Protein kinase dysfunction is accompanied with the access of numerous human diseases including cancer, inflammatory disorders, autoimmune syndromes, and cardiac diseases. Thus, the inhibition of the enzymes that initiate phosphorylation offers an approach to treat such diseases [116].