Browsing by Subject "Target validation"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    AD Informer Set: Chemical tools to facilitate Alzheimer's disease drug discovery
    (Wiley, 2022-04-20) Potjewyd, Frances M.; Annor-Gyamfi, Joel K.; Aubé, Jeffrey; Chu, Shaoyou; Conlon, Ivie L.; Frankowski, Kevin J.; Guduru, Shiva K.R.; Hardy, Brian P.; Hopkins, Megan D.; Kinoshita, Chizuru; Kireev, Dmitri B.; Mason, Emily R.; Moerk, Charles T.; Nwogbo, Felix; Pearce, Kenneth H.; Richardson, Timothy I.; Rogers, David A.; Soni, Disha M.; Stashko, Michael; Wang, Xiaodong; Wells, Carrow; Willson, Timothy M.; Frye, Stephen V.; Young, Jessica E.; Axtman, Alison D.; Medicine, School of Medicine
    Introduction: The portfolio of novel targets to treat Alzheimer's disease (AD) has been enriched by the Accelerating Medicines Partnership Program for Alzheimer's Disease (AMP AD) program. Methods: Publicly available resources, such as literature and databases, enabled a data-driven effort to identify existing small molecule modulators for many protein products expressed by the genes nominated by AMP AD and suitable positive control compounds to be included in the set. Compounds contained within the set were manually selected and annotated with associated published, predicted, and/or experimental data. Results: We built an annotated set of 171 small molecule modulators targeting 98 unique proteins that have been nominated by AMP AD consortium members as novel targets for the treatment of AD. The majority of compounds included in the set are inhibitors. These small molecules vary in their quality and should be considered chemical tools that can be used in efforts to validate therapeutic hypotheses, but which will require further optimization. A physical copy of the AD Informer Set can be requested on the Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) website. Discussion: Small molecules that enable target validation are important tools for the translation of novel hypotheses into viable therapeutic strategies for AD.
  • Thumbnail Image
    Item
    Evaluation of the therapeutic potential of Epigallocatechin-3-gallate (EGCG) via oral gavage in young adult Down syndrome mice
    (Springer, 2020-06-26) Goodlett, Charles R.; Stringer, Megan; LaCombe, Jonathan; Patel, Roshni; Wallace, Joseph M.; Roper, Randall J.; Biology, School of Science
    Epigallocatechin-3-gallate (EGCG) is a candidate therapeutic for Down syndrome (DS) phenotypes based on in vitro inhibition of DYRK1A, a triplicated gene product of Trisomy 21 (Ts21). Consumption of green tea extracts containing EGCG improved some cognitive and behavioral outcomes in DS mouse models and in humans with Ts21. In contrast, treatment with pure EGCG in DS mouse models did not improve neurobehavioral phenotypes. This study tested the hypothesis that 200 mg/kg/day of pure EGCG, given via oral gavage, would improve neurobehavioral and skeletal phenotypes in the Ts65Dn DS mouse model. Serum EGCG levels post-gavage were significantly higher in trisomic mice than in euploid mice. Daily EGCG gavage treatments over three weeks resulted in growth deficits in both euploid and trisomic mice. Compared to vehicle treatment, EGCG did not significantly improve behavioral performance of Ts65Dn mice in the multivariate concentric square field, balance beam, or Morris water maze tasks, but reduced swimming speed. Furthermore, EGCG resulted in reduced cortical bone structure and strength in Ts65Dn mice. These outcomes failed to support the therapeutic potential of EGCG, and the deleterious effects on growth and skeletal phenotypes underscore the need for caution in high-dose EGCG supplements as an intervention in DS.
  • Thumbnail Image
    Item
    Use of AD Informer Set compounds to explore validity of novel targets in Alzheimer's disease pathology
    (Wiley, 2022-04-12) Potjewyd, Frances M.; Annor-Gyamfi, Joel K.; Aubé, Jeffrey; Chu, Shaoyou; Conlon, Ivie L.; Frankowski, Kevin J.; Guduru, Shiva K.R.; Hardy, Brian P.; Hopkins, Megan D.; Kinoshita, Chizuru; Kireev, Dmitri B.; Mason, Emily R.; Moerk, Charles T.; Nwogbo, Felix; Pearce, Kenneth H., Jr.; Richardson, Timothy I.; Rogers, David A.; Soni, Disha M.; Stashko, Michael; Wang, Xiaodong; Wells, Carrow; Willson, Timothy M.; Frye, Stephen V.; Young, Jessica E.; Axtman, Alison D.; Medicine, School of Medicine
    Introduction: A chemogenomic set of small molecules with annotated activities and implicated roles in Alzheimer's disease (AD) called the AD Informer Set was recently developed and made available to the AD research community: https://treatad.org/data-tools/ad-informer-set/. Methods: Small subsets of AD Informer Set compounds were selected for AD-relevant profiling. Nine compounds targeting proteins expressed by six AD-implicated genes prioritized for study by Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) teams were selected for G-protein coupled receptor (GPCR), amyloid beta (Aβ) and tau, and pharmacokinetic (PK) studies. Four non-overlapping compounds were analyzed in microglial cytotoxicity and phagocytosis assays. Results: The nine compounds targeting CAPN2, EPHX2, MDK, MerTK/FLT3, or SYK proteins were profiled in 46 to 47 primary GPCR binding assays. Human induced pluripotent stem cell (iPSC)-derived neurons were treated with the same nine compounds and secretion of Aβ peptides (Aβ40 and Aβ42) as well as levels of phosphophorylated tau (p-tau, Thr231) and total tau (t-tau) peptides measured at two concentrations and two timepoints. Finally, CD1 mice were dosed intravenously to determine preliminary PK and/or brain-specific penetrance values for these compounds. As a final cell-based study, a non-overlapping subset of four compounds was selected based on single-concentration screening for analysis of both cytotoxicity and phagocytosis in murine and human microglia cells. Discussion: We have demonstrated the utility of the AD Informer Set in the validation of novel AD hypotheses using biochemical, cellular (primary and immortalized), and in vivo studies. The selectivity for their primary targets versus essential GPCRs in the brain was established for our compounds. Statistical changes in tau, p-tau, Aβ40, and/or Aβ42 and blood-brain barrier penetrance were observed, solidifying the utility of specific compounds for AD. Single-concentration phagocytosis results were validated as predictive of dose-response findings. These studies established workflows, validated assays, and illuminated next steps for protein targets and compounds.