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Nanomedicine Against COVID-19
Published in Hanadi Talal Ahmedah, Muhammad Riaz, Sagheer Ahmed, Marius Alexandru Moga, The Covid-19 Pandemic, 2023
Saima Zulfiqar, Zunaira Naeem, Shahzad Sharif, Ayoub Rashid Ch., M. Zia-Ul-Haq, Marius Moga
A suitable nanocarrier selection can eliminate many limitations in drug delivery, for example, toxic auristatin conjugates for hematological cancer treatment with the disadvantage of less drug pay-loads. This limitation was solved with the development of polymeric nanoparticles giving advantage of high drug (auristatin) payload for effective tumor repression [97]. Intolerable side effects of Aurora B kinase observed in a trial phase were avoided by combining it with polyethylene glycol/polylactide nanoparticles. Moreover, nucleic acid containing drugs also face limitations associated with intracellular delivery and unstable system of circulation [98–101]. Formulation of lipid nanoparticles loaded with nucleic acid drugs eliminated its conventional limitations with the aid of targeting the liver [102]. Similarly, silica mesopo-rous nanoparticles coated with lipid offered advantages of biocompatibility and more time for systematic circulation for the delivery of an antiviral drug, ML336. A high through output method, FIND was also reported, which screen these lipid nanoparticles for the in vivo delivery promoting nanocarriers as “immuno-oncology” therapeutics with the elimination of associated toxicity [103–105].
Precision Medicine and Future Therapeutics
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The cell cycle clock and cancerous growth are intimately linked – generally, when the cell cycle clock is disrupted, the cell proliferates excessively. Independently of the various cancer-specific gene mutations, the cell cycle clock can become deregulated by an alteration of the various growth factors, other proteins and small molecules which are essential for an orderly and timely operation of ‘the clock’. There appear to be a number of crucial points, particularly when the cell cycle progresses from the G1 phase to the S phase (Figure 1.5). It is here that a cell decides either to proceed further in the cycle or stop cycling and enter the G0 phase. This ‘decision point’ is termed the ‘restriction point’ (or R) and appears to be analogous to a ‘light switch’. Lastly, the molecular basis of the Aurora B kinase-dependent ‘abscission point’, whereby the intercellular bridge separates the two daughter cells and represents the final stage of cell cytokinesis, and the complex functions of the epsilon isoform of protein kinase C (PKCε) in mitosis and cytokinesis, is now emerging.
Discovery of a novel Aurora B inhibitor GSK650394 with potent anticancer and anti-aspergillus fumigatus dual efficacies in vitro
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Yuhua He, Wei Fu, Liyang Du, Huiqiao Yao, Zhengkang Hua, Jinyu Li, Zhonghui Lin
The pGEX-dual expression plasmid containing human (Hs.) Aurora B kinase domain (aa.54–344) and a C-terminal fragment of Hs.INCENP (aa.835–904) was obtained from Prof. Hongtao Yu (Department of Life Science, Westlake University). The cDNAs of Af.Aurora B kinase domain (aa.1–396, GenBank accession no. EDP54304.1) and the C-terminal fragment of Af.INCENP (aa.1200–1297, GenBank accession no. XP_033417438.1) was synthesised in Union Biotech (China). Protein expression and purification were performed as previously described31. Briefly, The recombinant proteins of Aurora B and INCENP were coexpressed in BL21 (DE3) pLysS competent cells. For protein purification, cells co-expressing GST-INCENP and Aurora B proteins were resuspended with lysis buffer containing 50 mM Tris-HCl, pH 8.0, 200 mM NaCl, 5% glycerol, and 0.05% Triton X-100. Cells were disrupted by French Pressure (Union Biotech, China) and the supernatants were collected after centrifugation. The Aurora B/Hs.INCENP complex proteins were pooled through Glutathione columns (Smart-Lifesciences, China). The GST tag was removed by homemade precision protease and the untagged proteins were further purified through a Superdex 200 10/300 GL column (GE Healthcare), with a running buffer containing 20 mM Tris-HCl, pH 8.0, 150 mM NaCl, and 1 mM DTT.
Aurora kinase inhibitors: a patent review (2014-2020)
Published in Expert Opinion on Therapeutic Patents, 2021
Previous studies have shown that Aurora A, B and C share a highly conserved C-terminal catalytic domain, but they have different functions in cell division. Preliminary evidence suggests that the selective of Aurora A or B inhibitors could avoid the toxicity of pan-Aurora kinase inhibitors and have better druggability. Moreover, Aurora B kinase inhibitors usually lead to the reduction of centrocytes. Therefore, it is generally believed that selective Aurora A kinase inhibitors have better chances of success in development than Aurora B kinase inhibitors, which will be clearer from the outcome of Phase III clinical trials of Aurora A selective inhibitor MLN8237 (alisertib). MLN8237 has the most ongoing Phase I and II clinical trials and has completed a phase III study in patients with relapsed/refractory PTCL.
Further insights into testicular germ cell tumor oncogenesis: potential therapeutic targets
Published in Expert Review of Anticancer Therapy, 2020
Paolo Chieffi, Marco De Martino, Francesco Esposito
This kinase phosphorylates the H3 histone at serine 10, regulating chromosome condensation, alignment, and segregation. Also, spindle checkpoint function and cytokinesis are controlled by Aurora B kinase [54]. Furthermore, centrosome amplification has been connected to aneuploidy of TGCTs as reported by several research works [54]. Notably, in GC1 and TCam-2 testis-derived cell lines, the cell growth rate is strongly reduced following the inhibition of Aurora B kinase activity [55]. Definitely, AZD1152, ZM447439, Hesperadin 8, and VX-680 are Aurora B inhibitors that have been tested [55,56]. In particular, AZD1152 was tested in an extensive panel of human cancer xenograft considerably preventing the growth of tumors. Importantly, AZD1152 and other Aurora B inhibitors (ZM2, ZM3, GSK1070916) which block the phosphorylation of H3 histone on serine 10 [56], then abolishing cell division, show a reversible neutropenia as a main side effect, and they are in early clinical evaluation [55].