Browsing by Author "Anderson, Jared"

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    Advances in Ionic Liquid-Based Stationary Phases and Sorbent Materials for Chromatography and Sample Preparation (2020-02-07)
    (2020) Anderson, Jared; University of Minnesota Duluth. Department of Chemistry and Biochemistry
    Ionic liquids (ILs) can be designed to exhibit unique properties for their use in a number of applications in analytical and bioanalytical chemistry. This talk will focus on the design and synthesis of ILs, magnetic ionic liquids (MILs), and polymeric ionic liquids (PILs) as well as the use of these materials in a number of applications within multidimensional chromatography and sample preparation. A series of monocationic/dicationic ionic liquid-based and silver-containing stationary phases were evaluated as secondary columns in comprehensive two-dimensional gas chromatography (GCxGC) for the separation of aliphatic hydrocarbons from kerosene as well as the separation of olefins from paraffins. Finally, nucleic acids are biopolymers that constitute important diagnostic molecules for a broad range of applications from clinical testing to forensic analysis. A major challenge faced by DNA and RNA analysis techniques is the selective extraction of particular nucleic acid sequences using rapid and sensitve methodologies. It will be shown that ion-tagged oligonucleotides (ITOs) can be used in conjunction with MILs to efficiently capture DNA sequences from complex samples. The ITOs can be created through thio-lene "click" chemistry and the nature of the ion tag can influence the partitioning of the ITO to the hydrophobic MIL. This novel liquid-phase approach towards sequence-selective DNA capture provides superior extraction efficiencies to conventional magnetic bead technology as well as a platform for using external fields to manipulate the liquid droplets.
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    Development of targeted degraders and allosteric ligands of NF-κB inducing kinase (NIK): synthesis, biochemical, and biophysical evaluation studies
    (2025-01) Anderson, Jared
    Kinases are commonly targeted in drug discovery campaigns due to their roles in many signaling pathways. Many kinase inhibitors work by occupying the orthosteric binding site and preventing ATP from being used as a substrate. All of the known efforts for targeting the disease relevant kinase NF-κB inducing kinase (NIK) have used a similar approach. This thesis will discuss our efforts in developing novel degraders of NIK by repurposing known orthosteric inhibitors and the development of the first known allosteric NIK ligands and characterization of their binding mode. Dysregulation of NIK has been implicated in a variety of cancers, including multiple myeloma, and immune disorders. Native regulation of NIK involves constant polyubiquitination and subsequent degradation of the protein by the 26s proteasome. Chapter 2 will discuss our efforts towards reinstating this degradation mechanism by using proteolysis targeting chimera (PROTAC) technology. Unfortunately, none of these compounds were able to degrade NIK in multiple myeloma cell lines. These findings serve as a case study into the difficulties of targeted-protein degradation. An allosteric-biased fragment-based screening effort leading to novel allosteric NIK ligands will be discussed in Chapter 3. The primary hit compound 3.1 displayed a Kd of 130 μM and did not show any competition with a non-hydrolysable ATP analogue (AMP-PNP) by NMR or SPR assays. Synthesis of analogues lead to compound 3.4 bearing a cyclopropyl ring and having a binding affinity of 40 μM. Efforts towards tighter binders was difficult due to the lack of structural information. Therefore, Chapter 4 discusses how the covalent probe compound 4.1 was used to adduct a cysteine near the allosteric binding site that was subsequently uncovered using LC-MS-MS peptide mapping experiments. It was uncovered that compound 4.1 was able to selectively adduct to C573 in this allosteric site on the catalytic domain of NIK. Finally, Appendix A focuses on early efforts towards the discovery of allosteric NIK inhibitors from computational screening efforts from our collaborators in the Amaro lab at the University of California – San Diego. While none of these compounds were able to inhibit NIK activity, this served as the starting point that lead to the findings of both Chapter 3 and Chapter 4.
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    Golden Eagles Fall to Beavers in Thriller on Friday Night
    (University of Minnesota Crookston, 2021-02-19) Anderson, Jared