Discovery of novel targets in the hedgehog signaling pathway

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dc.contributor.advisorWaldmann, Herbert
dc.contributor.authorPatil, Sumersing
dc.contributor.refereeDehmelt, Leif
dc.date.accepted2017-11-08
dc.date.accessioned2018-12-03T07:17:08Z
dc.date.available2018-12-03T07:17:08Z
dc.date.issued2017
dc.description.abstractThe Hedgehog (Hh) signaling pathway is vital for organ development and tissue patterning during embryogenesis. However, its inappropriate activation is linked to several types of cancers. Therefore, development of small molecule modulators of Hh pathway is of utmost importance in the field of cancer research. A high-throughput cell-based screen in C3H/10T1/2 cells that monitor osteogenesis upon activation of Hh signaling identified YCL-220, RKN-1043 and MJD-1314 as inhibitors of Hh signaling. Orthogonal assays revealed YCL-220, RKN-1043 and MJD-1314 as potent inhibitors of GLI transcription factor-mediated Hh signaling pathway. Mechanistic insights showed that YCL-220 acts as a SMO antagonist that inhibits SMO localization to cilia while RKN-1043 and MJD-1314 acts independent of SMO. Chemical proteomics experiments led to identification of Rho GDP-dissociation inhibitor-1 (RHOGDI1) and methylthioadenosine phosphorylase (MTAP) as a potential target for RKN-1043 and MJD-1314, respectively. Genetic alterations of RHOGDI1 and MTAP revealed their involvement in the regulation of Hh signaling pathway. The work presented in this thesis led to the identification of novel Hh signaling inhibitors and uncovered novel players in Hh signaling pathway. The approach followed in this study stresses on the importance of using a combination of methods for identification and validation of small-molecule targets in order to establish the mechanism of action of small molecule modulators.en
dc.identifier.urihttp://hdl.handle.net/2003/37822
dc.identifier.urihttp://dx.doi.org/10.17877/DE290R-19817
dc.language.isoende
dc.subjectHedgehog signalingen
dc.subjectTarget identificationen
dc.subjectSmall moleculeen
dc.subjectScreeningen
dc.subject.ddc570
dc.subject.ddc540
dc.subject.rswkHedgehogen
dc.titleDiscovery of novel targets in the hedgehog signaling pathwayen
dc.typeTextde
dc.type.publicationtypedoctoralThesisde
dcterms.accessRightsopen access
eldorado.secondarypublicationfalsede

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