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Small-Molecule Inhibitors Targeting Receptor Tyrosine Kinases in Cancer
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Mohammad Hojjat-Farsangi, Gholamreza Khamisipour
Hepatocyte growth factor/scatter factor (HGF/SF) has been noted as a multi-functional growth factor and is a MET ligand that binds to the extracellular region of MET oncogene and induces receptor dimerization and transphosphorylation of tyrosine residues 1234 and 1235 within the kinase domain followed by structural alteration within the receptor. Phosphorylation of tyrosine 1349 and 1356 residues at C-terminal region of MET are also required for MET signaling pathway (Graveel et al., 2013). In patients with hereditary papillary renal carcinoma, mutations flank the tyrosine residues 1234 and 1235 may induce the constitutive activation of MET oncogene (Schmidt et al., 1997). RAS/RAF/MEK/ERK, PI3K/AKT, and SRC/FAK are the main signaling pathways that are activated following MET activation. Activation of these signaling pathways increase cell proliferation, motility, survival, and angiogenesis (Rosen et al., 2011).
Advances of engineered extracellular vesicles-based therapeutics strategy
Published in Science and Technology of Advanced Materials, 2022
Hiroaki Komuro, Shakhlo Aminova, Katherine Lauro, Masako Harada
Hydrophobic insertion is a widely used method for liposome-based drug delivery and can be applied to engineering EVs as well [132–136]. This method allows target molecules to functionalize the EV surface using EV membrane components mainly consisting of phospholipids, cholesterol, and glycolipids, without the need for special reactions or reagents. In particular, polyethylene glycol (PEG)-linked phospholipids have been used in a variety of nanomaterials to develop targeted drug delivery [137]. PEG-phospholipids have a hydrophilic tail of PEG and a hydrophobic head of phospholipids, such as distearoyl phosphatidylethanolamine (DSPE) and dimyristoyl-phosphatidylethanolamine (DMPE). The circulation persistence of these PEG-phospholipids can be adjusted by both the length of the PEG chain and the graft density [132,138]. The hydrophobic molecules insertion of the EV membrane is mainly used with in the composition of phospholipid anchor, PEG spacer, and targeting molecules via hydrophobic interaction. For example, it has been reported that DSPE-PEG conjugated to biotin and avidin [139], anisamide (AA) (target sigma receptor) [136], EGa1 (EGFR targeting nanobody) [133], tyrosine-protein kinase met (c-Met) [140], RGD (Arg-Gly-Asp-D-Tyr-Lys monobody, integrin αvβ3) [141,142], cyclo-RGD (cRDG) [143], anti-EGFR-iRGD (recombinant protein) [144] on EVs was successful in enhancing targeting. However, the stability of the inserted molecule in vivo using this method has yet to be understood [145].
MicroRNA-122 overexpression promotes apoptosis and tumor suppressor gene expression induced by microcystin-leucine arginine in mouse liver
Published in International Journal of Environmental Health Research, 2022
Rui Wang, Haohao Liu, Xingde Du, Ya Ma, Zhihui Tian, Shiyu Zhang, Linjia Shi, Hongxiang Guo, Huizhen Zhang
More and more studies showed that MC-LR can cause a variety of organ toxicity, such as hepatotoxicity, intestinal toxicity, renal toxicity, neurotoxicity, and reproductive toxicity McLellan and Manderville (2017). Among various organs, the liver is the primary target organ after MC-LR enters into the body. Studies have found that approximately 50–70% of MC-LR eventually enters the liver through the blood McLellan and Manderville (2017). Epidemiological studies have shown that the accumulation of MC-LR can cause various liver damage Zeng et al. (2017). Even the level of MC-LR in serum had a great positive correlation with the risk of liver cancer Zheng et al. (2017). MC-LR exposure can lead to changes in tumor-related genes in liver cells, such as increasing expressions of oncogenes (c-fos, c-jun, c-myc, and c-met) and decreasing expression of tumor suppressor gene PTEN Li et al. (2017).
Metal-free domino amination-Knoevenagel condensation approach to access new coumarins as potent nanomolar inhibitors of VEGFR-2 and EGFR
Published in Green Chemistry Letters and Reviews, 2021
Essam M. Eliwa, Marcel Frese, Ahmed H. Halawa, Maha M. Soltan, Larissa V. Ponomareva, Jon S. Thorson, Khaled A. Shaaban, Mohamed Shaaban, Ahmed M. El-Agrody, Norbert Sewald
The most potent one against KB-3-1 and A549 cell lines (Table 2), 4e showed 1.2 and 2.5-fold inactivation toward VEGFR-2 and EGFR, respectively. Moderate activities were also obtained by 5e against the examined kinases. Regarding COVID-19, in silico studies have predicted higher affinity between the viral spike glycoprotein (S) and the inhibitors of the hepatocyte growth factor receptor (HGFR/c-MET), VEGFR and EGFR [56]. Consequently, exploring more agents against the above receptors is more than welcome.