92 research outputs found
Towards a RIOK2 chemical probe: cellular potency improvement of a selective 2-(acylamino)pyridine series
No full textRIOK2 is an understudied kinase associated with a variety of human cancers including non-small cell lung cancer and glioblastoma. No potent, selective, and cell-active chemical probe currently exists for RIOK2. Such a reagent would expedite re-search into the biological functions of RIOK2 and validate it as a therapeutic target. Herein, we describe the synthesis of naphthyl–pyridine based compounds that have improved cellular activity while maintaining selectivity for RIOK2. While our compounds do not represent RIOK2 chemical probes, they are the best available tool molecules to begin to characterize RIOK2 function in vitro.Doctor of Pharmac
Editorial: Human Protein Kinases: Development of Small-Molecule Therapies
No full textHuman protein kinases are ubiquitously expressed throughout the human body and embedded in signaling pathways that mediate diverse biology. When their function becomes aberrant due to mutation(s) and/or changes in expression, resultant kinase dysfunction can propagate disease. Fortunately, kinases represent highly tractable proteins that can be pharmacologically inhibited to impact disease progression. Capitalizing on this feature, industrial and academic labs have pushed more than 80 small molecule kinase inhibitors through FDA approval, resulting in the distinction of kinase inhibitors as one of the most important drug classes. While most of these kinase-targeting drugs have been approved for oncological indications, kinase function can be similarly modulated to impact other progressive diseases, such as those impacting the heart or brain. Another aspect of these approved drugs to consider is their binding mode. There are a few examples, such as trametinib, asciminib, and deucravacitinib, of FDA-approved kinase drugs that bind to an allosteric site outside of the ATP-binding pocket to elicit kinase inhibition. These allosteric sites can be proximal to (type III kinase inhibitor) or distal from (type IV kinase inhibitor) the ATP-binding pocket. A deeper look into the kinase targets of FDA-approved drugs reveals that they inhibit only a small fraction of the human kinome. In light of the historic success of drugging human kinases, one may consider whether inhibiting those kinases in the lesser studied portion of the human kinome could result in new drugs and/or expand the diseases that can be assuaged through kinase inhibition
Editorial: Human Protein Kinases: Development of Small-Molecule Therapies
No full textHuman protein kinases are ubiquitously expressed throughout the human body and embedded in signaling pathways that mediate diverse biology [...
EXPLORING THE MUCIN GLYCAN-DEGRADING GLYCOSIDE HYDROLASE LANDSCAPE IN THE GUT MICROBIOME AND TARGETING HSP90 IN MICROBIAL PATHOGENS
No full textThe human gut microbiota consists of trillions of microorganisms that collectively encode approximately 150 times more genetic information than the human genome1,2. These microbes influence host health and disease, in part by metabolizing molecules that reach the gastrointestinal (GI) tract, including host-derived glycoproteins (mucins, immunoglobulins) and glycoconjugates (neurotransmitters, phytochemicals, therapeutics). Gut microbial glycoside hydrolases (GH) play a key role in metabolizing these molecules, removing the sugars conjugated to them for fermentation by the bacteria. Understanding the mechanisms by which the gut microbiota metabolizes these molecules is crucial given the implications in disease states, drug efficacy, and toxicity. We investigated the role α-fucosidases (FUCs) in mucin-glycan degradation. We biochemically characterized gut microbial FUCs using a panel of fucose containing substrates, showing that they possess strict substrate preferences. Additionally, we characterized their activity against mucus produced by human colonic epithelial cells and identified a FUC subfamily capable of liberating fucose from human colonic mucus. These findings implicate this subfamily as a key initiator of mucin-glycan degradation in the gut. Then, we examined gut microbial β-galactosidases (GAL) against a panel of galactose-containing disaccharides found in mucin glycan structures. We characterized diverse GALs against these disaccharides and found that they have variable substrate activities. We investigated their susceptibility to small molecule inhibitors, finding that a β-glucuronidase (GUS) inhibitor potently targets GALs. Additionally, we found that this molecule potently inhibits GALs extracted from human fecal samples. Next, we investigated the molecular chaperone, Hsp90, and its orthologs in microbial pathogens as an avenue for antimicrobial development. We report the first crystal structure of the prokaryotic Hsp90 ortholog, High temperature protein G (HtpG), from Borrelia burgdorferi, the microbe responsible for Lyme Disease, bound to a high affinity ligand. Using structural insights, we developed a tethered inhibitor capable of localizing a photoactivable toxin to live Borrelia and kill the spirochete upon light activation. There is a growing threat of antifungal resistance, and it is necessary that we develop new antifungal drugs. Targeting Hsp90 produced by pathogenic fungi is a promising avenue for antifungal development. We conducted a fragment screen against Hsp90 produced by the pathogenic fungi, Candida albicans, and provide structural rationale for the selective binding of an Hsp90 inhibitor. These findings highlight a region of Hsp90 that is exploitable for selective inhibitor design.Doctor of Philosoph
Discovery and optimization of narrow spectrum inhibitors of Tousled like kinase 2 (TLK2) using quantitative structure activity relationships
No full textThe oxindole scaffold has been the center of several kinase drug discovery programs, some of which have led to approved medicines. A series of two oxindole matched pairs from the literature were identified where TLK2 was potently inhibited as an off-target kinase. The oxindole has long been considered a promiscuous kinase inhibitor template, but across these four specific literature oxindoles TLK2 activity was consistent, while the kinome profile was radically different ranging from narrow to broad spectrum kinome coverage. We synthesized a large series of analogues, utilizing quantitative structure-activity relationship (QSAR) analysis, water mapping of the kinase ATP binding sites, kinome profiling, and small-molecule x-ray structural analysis to optimize TLK2 inhibition and kinome selectivity. This resulted in the identification of several narrow spectrum, sub-family selective, chemical tool compounds including 128 (UNC-CA2-103) that could enable elucidation of TLK2 biology.</p
A comparative study of three river systems leading into Nootka Sound, British Columbia: implications for winter salmon populations
No full textSenior thesis written for Oceanography 445[author abstract] Data collection consisted of plankton tows, and temperature, pH, and salinity readings taken at multiple stations within the Tahsis, Zeballos, and Gold Rivers located in Vancouver Island, British Columbia in December, 2015. These samples and data from previous research were used to analyze which river system could best support juvenile, winter salmon. Salinity and pH do not appear to be driving factors in these river systems in respect to salmon prey abundance, while temperature could affect salmon survival. All three rivers were composed of like species with the Tahsis and Zeballos rivers having the most similar compositions of organisms. Salmon prey of interest included species of Plecoptera, Cladocera, Nauplii, and copepods from the orders Calanoida and Cyclopoida. Species richness and diversity varied across all three areas of study. All three rivers could be suitable for winter salmon, but the Tahsis River could best support winter salmon populations if temperature and prey composition are the most influential factors on salmon growth and survival.University of Washington School of Oceanograph
Editorial: The next generation of tools and technologies for studying human neurons in a dish
No full textDespite their prevalence, disorders of the brain, including neurodevelopmental, neurodegenerative, and other mental illnesses, have historically been some of the most challenging to treat. The enormous economic burden coupled with a paucity of curative therapies highlights an urgent need for new approaches and targets to tackle these diseases. One biologically relevant and transformative method that has been employed is the use of induced pluripotent stem cells (iPSCs) to generate neurons that closely mimic those found within the human brain (Mohamed et al., 2019). Advances in this area have enabled investigators to readily grow many of the cell types found within the human brain on a dish, increasing our understanding of mechanisms and targets that are implicated in these diseases and helping to facilitate translational efforts (Fermini et al., 2018)
SGC-CK2-1: The First Selective Chemical Probe for the Pleiotropic Kinase CK2
No full textBuilding upon a wealth of published knowledge surrounding the pyrazolopyrimidine scaffold, we designed a small library around the most selective small molecule CK2 inhibitors reported. Through extensive evaluation of this library we identified inhibitor 24 (SGC-CK2-1) as a potent, selective, and cell-active CK2 chemical probe. Remarkably, despite years of research pointing to CK2 as a key driver in cancer, our probe did not elicit an antiproliferative phenotype in cell lines tested. While many publications have attempted tocharacterize CK2 function, CK2 biology is complex and a high-quality chemical tool like SGC-CK2-1 will aid in connecting CK2 functions to phenotypes
- …
