Identification and characterization of inhibitors of hedgehog-induced osteoblast differentiation
| dc.contributor.advisor | Waldmann, Herbert | |
| dc.contributor.author | Flegel, Jana Erika | |
| dc.contributor.referee | Rauh, Daniel | |
| dc.date.accepted | 2022-05-25 | |
| dc.date.accessioned | 2022-07-13T11:47:08Z | |
| dc.date.available | 2022-07-13T11:47:08Z | |
| dc.date.issued | 2022 | |
| dc.description.abstract | Hedgehog (Hh) signaling is one of the major pathways that is essentially required during embryonic development in vertebrates. Dysregulation during embryogenesis has been linked to severe developmental malformations including cyclopia and holoprosencephaly. Moreover, aberrant Hh signaling has been associated with several types of cancer, such as medulloblastoma and basal cell carcinoma. Over the past 40 years, studies have provided many insights into the current understanding of the Hh signaling pathway. Due promising potential for therapeutic modulation of this pathway, identification of small molecule modulators of Hh signaling is in high demand. Throughout this thesis, six compounds were identified as potent inhibitors of Hh-dependent osteogenesis during a phenotypic screening. Five of these compounds inhibited GLI2/3-dependent reporter activity and expression of Hh target genes and were thus classified as novel Hh pathway inhibitors. While four compounds, a Furo[3,2-b]pyridine, quinoline, pyrroloquinoline and 20-membered macrocycle derivative bind to the key signaling molecule smoothened (SMO), one compound, a 4-arylisoquinolone does not bind to the heptahelical bundle of this protein. An 8-oxotetrahydroprotoberberine derivate, termed Picoberin, inhibited Hh-dependent osteogenesis with a single-digit picomolar IC50 but did not modulate canonical Hh signaling. Despite its remarkable bioactivity, this small molecule was not cytotoxic at high concentrations in several cell lines. Global transcriptome and proteome profiling revealed that Picoberin activates Aryl hydrocarbon Receptor (AhR) signaling and led to the identification of AhR as the potential protein target. Subsequent functional evaluation of the influence of Picoberin on AhR signaling in several cell lines confirmed this target hypothesis. Moreover, chemical validations and genetic AhR depletion linked Picoberin mediated activation of AhR signaling to inhibition of Hh-dependent osteogenesis. Additionally, results obtained in this thesis provide evidence for crosstalk of AhR and Hh signaling and a functional role for AhR during osteoblast differentiation. AhR regulates xenobiotic metabolism as well as numerous physiological processes such as immune cell function, stem cell maintenance, and differentiation. Dysregulation of this ligand-activated transcription factor is observed in several diseases, including cancer. Historically, AhR is linked to mainly toxic effects. However, recent approval of the AhR agonist Tapinarof for treatment of plaque psoriasis and several studies exploring AhR in cancer provide evidence for potential therapeutic applications of AhR modulators. Picoberin could not only serve as a tool compound for AhR research but may potentially also provide a starting point for the development of further therapeutic AhR agonists. | en |
| dc.identifier.uri | http://hdl.handle.net/2003/40988 | |
| dc.identifier.uri | http://dx.doi.org/10.17877/DE290R-22837 | |
| dc.language.iso | en | de |
| dc.subject | Hedgehog | en |
| dc.subject | Osteogenesis | en |
| dc.subject | Differentiation | en |
| dc.subject.ddc | 570 | |
| dc.subject.ddc | 540 | |
| dc.subject.rswk | Osteogenese | de |
| dc.title | Identification and characterization of inhibitors of hedgehog-induced osteoblast differentiation | en |
| dc.type | Text | de |
| dc.type.publicationtype | doctoralThesis | de |
| dcterms.accessRights | open access | |
| eldorado.secondarypublication | false | de |