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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
The term “oncogenic addiction” was coined by Weinstein (Weinstein, 2000) in 2000 and demonstrated that cancer cells might show addiction to an oncogenic signaling molecule or pathway to sustain tumor activity such as survival and proliferation. Various enzymes such as tyrosine/serine/threonine kinases, are known to be crucial for the process of oncogenesis. Kinases are protein enzymes that phosphorylate and transfer a phosphate group from adenosine 3 phosphates (ATP) to special amino acid residues, including tyrosine, serine, or threonine. Phosphorylation of proteins is one of the most vital events that regulate cellular activities in a precise way. Overall, phosphorylation of oncoproteins is a necessary phenomenon for tumor cells regulation and activation (Tsai and Nussinov, 2013).
Biomems
Published in Simona Badilescu, Muthukumaran Packirisamy, BioMEMS, 2016
Simona Badilescu, Muthukumaran Packirisamy
A kinase is a protein enzyme that adds a phosphate onto a molecule, though typically only proteins. The phosphorylated molecule can be another protein, the kinase itself (autophosphorylation), or any other molecule. The source for the phosphate is terminal phosphate, which is called the gamma (g) phosphate from ATP.
Zinc(II) derivatives of N, O containing Schiff bases: synthesis, characterization, computational and biological studies
Published in Journal of Coordination Chemistry, 2023
Saadia Batool, Anham Zafar, Muhammad Athar, Mehwish Mehmood, Muhammad Nawaz Tahir, Ihsan-Ul Haq, Sayed Sikander Azam
Protein kinase inhibition assay has been performed for I1–I9 and 1–9 using surfactin as positive control showing maximum bald zone of 30.3 mm and DMSO as a negative control; the data are tabulated in Table 7. Among the free ligands, I4 and I6 displayed significant bald zones of 16 and 14 mm, respectively, whereas I5 and I7 showed clear zones of 14 mm. Among the complexes, only 1–3 possessed significant bald zones of 18, 20, and 14 mm; 2 exhibits highest bald inhibition zone because of its naphthalene group that facilitates the pi-electron resonance. Bald and clear inhibition zones close to 20 mm indicate moderate inhibitory potential and cytotoxicity, respectively. Basically, the strain of eukaryotic Streptomyces 85E is used to perform protein kinase inhibition activity, as it delivered a clear demonstration of cytotoxic nature as well as anticancer potential of all tested compounds. Main function of protein kinases (PTKs) is to normalize the biological activity of proteins via phosphorylation of amino acids by using ATP as phosphate source. Protein undergoes a conformational change from inactive to an active state, and the inhibitors of these enzymes are particularly involved in discontinuing their function to stop the spread of cancerous cells [46]. The presented data for ligands and their metal complexes may act as scaffold for drug development projects in future. The protein kinase inhibition potential for all screened compounds is depicted in Figure S6 as supplementary file.
Deciphering the resistance mechanism of RET kinase mutant against vandetanib and nintedanib using molecular dynamics simulations
Published in Journal of Experimental Nanoscience, 2021
Guodong Zheng, Shenqian Xu, Wuxia Liu, Tingting Du, Jingfeng Zhang, Minyu Li, Chen Cai, Hong Shi
However, the emergence of drug-resistant mutations represents an upcoming challenge, as a vast amount of cases in clinic and in laboratory have been reported [20]. For example, the RETG810A mutant that has an alteration of glycine residue to alanine at the ATP-binding pocket has recently identified as a vandetanib-resistant target [21]. Since mutations on RET kinase domain may result in the drug resistance to one or several specific RET TKIs, current solutions to overcome the challenge are by screening other potentially active compound among the clinically relevant RET TKIs. As such, another TKI nintedanib, which was previously designed for targeting angiokinases (e.g. VEGFR), was found to be effective in inhibiting RETG810A [21, 22].
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].