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  • Exploring Novel Approaches Towards Anti-Cancer Galectin-3 Chemotherapeutics

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    Ross, Ashleigh_Final Thesis_redacted.pdf (8.178Mb)
    Author(s)
    Ross, Ashleigh R.
    Primary Supervisor
    Grice, Irwin D
    Other Supervisors
    von Itzstein, Mark
    Year published
    2020-05-01
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    Abstract
    Galectins are β-galactoside binding proteins first isolated in 1975 from the organ tissue of an electric eel. Since then, 15 galectins have been identified across a variety of species offering quite a number of biological functions. These lectins bind to saccharides in the nucleus, cytosol and extracellular matrix (ECM) to initiate intracellular signal cascades or to mediate cell-to-cell and cell-to-ECM adhesion. Of the 12 galectins found in humans, several are implicated in inflammatory diseases and cancer progression. Galectin-3 in particular, is often exploited by cancerous cells to promote cell proliferation, angiogenesis, ...
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    Galectins are β-galactoside binding proteins first isolated in 1975 from the organ tissue of an electric eel. Since then, 15 galectins have been identified across a variety of species offering quite a number of biological functions. These lectins bind to saccharides in the nucleus, cytosol and extracellular matrix (ECM) to initiate intracellular signal cascades or to mediate cell-to-cell and cell-to-ECM adhesion. Of the 12 galectins found in humans, several are implicated in inflammatory diseases and cancer progression. Galectin-3 in particular, is often exploited by cancerous cells to promote cell proliferation, angiogenesis, immune evasion, metastasis and ultimately cause multi drug resistance to current anti-cancer therapeutics. Inhibition or eradication of galectin-3 would likely diminish its tumour promoting functions, while also increasing the efficacy of modern anticancer treatments formerly proving ineffective. Development of novel high-affinity galectin-3 inhibitors is of great interest when considering the efficacy of a potential galectin-3 targeting anticancer therapeutic. As the natural ligand for galectin-3 is N-acetyl lactosamine (LacNAc), carbohydrate-based inhibitors have been thoroughly investigated, with some ligands offering nanomolar binding affinity and exceptional selectivity for galectin-3 over galectin-1. A component of this research investigated a small library of iminosugars as a potential novel carbohydrate scaffold for a galectin-3 inhibitor. Iminosugars are currently approved therapeutics for a number of biological conditions with excellent safety profiles, offering an attractive target to explore for novel drug design. Molecular docking of the iminosugar scaffold into the galectin-3 carbohydrate recognition domain (CRD), displayed hydrogen bonding and stacking interactions similar to a natural monosaccharide ligand of galectin-3, galactose. This suggested the iminosugars will bind to the CRD of galectin-3, however, saturation transfer difference (STD) NMR analysis did not provide information to support the binding of the iminosugars with galectin-3. This may be due to the small scaffold of the monosaccharide iminosugar, weakening its binding affinity and limiting the detection of an STD NMR signal. It is recommended that further analysis of the binding potential of these sugars is analysed by surface plasmon resonance (SPR) or isothermal titration calorimetry (ITC) as the initial molecular docking analysis revealed promising results for the use of iminosugars as a novel galectin-3 inhibitor scaffold. Proteolysis Targeting Chimera or PROTAC, is a relatively new nanotechnology-based approach to bring a target protein of interest into close special proximity with an E3-ligase, to provide not only inhibition but therapeutic destruction of the target protein, via hijacking of the ubiquitin-proteasome system. This approach is specific, versatile and was investigated in this research to achieve therapeutic destruction of galectin-3. A PROTAC was designed containing: (i) a potent monosaccharide galectin-3 inhibitor linked via, (ii) a polyethylene glycol (PEG) linker, to (iii) a thalidomide moiety known to recruit the CRBN E3-ligase. Synthesis of the monosaccharide galectin-3 inhibitor was successfully performed following mostly published protocols, with several refinements required to improve published yields. The thalidomide-linker moiety was synthesised almost to completion, although degrading before the final synthetic step could be carried out. Unfortunately, time did not permit a further attempt at re-synthesising the thalidomide-linker moiety. Therefore, the galectin-3 targeting PROTAC could not be completed. However, competition STD NMR analysis of the synthesised galectin-3 inhibitor confirmed successful binding to galectin-3, that was stronger than lactose. Although the synthesis of the PROTAC target was not completed, molecular dynamic (MD) simulations investigating the galectin-3 targeting PROTAC supported the proposed positioning of the thalidomide-linker moiety attached to the monosaccharide galectin-3 inhibitor, in that it would not disrupt the inhibitor binding into the galectin-3 CRD. This was concluded as the terminal end of the carbohydrate inhibitor protruded outside the binding site to provide an optimal point of attachment for the linker. In conclusion, the research work presented here offers insight into (i) the therapeutic potential of iminosugars as a novel galectin-3 inhibitor scaffold, (ii) the synthesised modified galectin-3 inhibitor was confirmed to bind more strongly than lactose to galectin-3, and (iii) MD simulations of the galectin-3 targeting PRTOAC provided positive results for further investigation as a potential therapeutic. Overall, this work has provided various avenues for future exploration towards the development of efficacious anti-cancer galectin-3 chemotherapeutics.
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    Thesis Type
    Thesis (Masters)
    Degree Program
    Master of Medical Research (MMedRes)
    School
    School of Medical Science
    DOI
    https://doi.org/10.25904/1912/1361
    Copyright Statement
    The author owns the copyright in this thesis, unless stated otherwise.
    Subject
    Galectin-3
    high-affinity inhibitors
    iminosugars
    inhibitor scaffold
    anti-cancer chemotherapeutics
    Publication URI
    http://hdl.handle.net/10072/393973
    Collection
    • Theses - Higher Degree by Research

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