Discovery and Characterization of Novel Chemical Inhibitors of Wnt Ligand Production with Implications for Anti-Cancer Therapy
| dc.contributor.advisor | Lum, Lawrence | en |
| dc.creator | Dodge, Michael E. | en |
| dc.date.accessioned | 2012-07-20T18:52:49Z | |
| dc.date.available | 2012-07-20T18:52:49Z | |
| dc.date.issued | 2012-07-20 | |
| dc.description.abstract | The widespread and indispensable nature of Wnt morphogens during early development has long been a focal point of embryogenesis research. More recently, pathway activation has been uncovered in adult stem cell niches and cancers arising from associated tissues. Consequently, interest has shifted towards achieving chemically based control over aberrant pathway responses, with the ultimate goal of creating therapeutic utility. To this end our laboratory screened a diverse 200K compound library using cell based transcriptional reporters and uncovered several classes of small molecules that modulate distinct Wnt regulatory nodes. One class in particular, termed IWP (Inhibitor of Wnt Production), represents the first specific chemical inhibitors of a Membrane Bound O-Acyltransferase family member: Porcupine. Herein we postulate that IWPs function by binding to and disrupting Porcupine?s active site, preventing subsequent acylation of Wnt ligands necessary for downstream pathway activation. Further SAR studies reveal first generation IWP lead structures to be superior at this task in vitro, with even modest structural changes negatively impacting compound activity. Finally, we propose that due to Porcupine?s upstream position within the Wnt pathway, IWP administration has the potential to disrupt oncogenic contributions made by recently uncovered non-canonical Wnt signaling events. Together these findings advance our understanding of Wnt chemical tractability with long-term implications for targeted therapies. | en |
| dc.identifier.oclc | 809539265 | |
| dc.identifier.uri | https://hdl.handle.net/2152.5/1022 | |
| dc.language.iso | en | en |
| dc.subject | Wnt Proteins | en |
| dc.subject | Neoplasms | en |
| dc.subject | Hedgehog Proteins | en |
| dc.title | Discovery and Characterization of Novel Chemical Inhibitors of Wnt Ligand Production with Implications for Anti-Cancer Therapy | en |
| dc.type | Thesis | en |
| dc.type.material | Text | en |
| thesis.date.available | 2014-01-14 | |
| thesis.degree.department | Graduate School of Biomedical Sciences | en |
| thesis.degree.discipline | Cell Regulation | en |
| thesis.degree.grantor | UT Southwestern Medical Center | en |
| thesis.degree.level | Doctoral | en |
| thesis.degree.name | Doctor of Philosophy | en |
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