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AuthorGarcía Reyes, Balbinadc.contributor.author
Date of accession2018-02-06T09:37:34Zdc.date.accessioned
Available in OPARU since2018-02-06T09:37:34Zdc.date.available
Year of creation2017dc.date.created
Date of first publication2018-02-06dc.date.issued
AbstractCasein kinase 1 (CK1) proteins phosphorylate a broad range of substrate proteins and are involved in many physiological processes such as metabolism, transcription, cell cycle progression, apoptosis, and differentiation. The development and characterization of new potent CK1-specific inhibitors might be of interest for new therapeutical concepts in pathological conditions. So far, several CK1 inhibitor compounds have been identified and some of them have already been proven their efficacy in animal models. Still, designing powerful and isoform-specific inhibitors constitutes a challenge. CK1δ inhibition was accomplished in this work through two approaches: the informed design of specific CK1 inhibitors and the repurposing of a well-known small molecule commercially available. The compounds were initially assayed to check for their ability to selectively inhibit CK1 isoforms. Most of the assayed compounds inhibited the activity of CK1δ and CK1ε in a nanomolar range. Compounds 118, 122, 124 and 125 showed the most distinct inhibitory effects. The compounds also showed to act in an ATP-competitive manner. When assayed against a gatekeeper mutant form of CK1δ, the compound did not show differences in inhibitory ability. Compounds 118, 123 and 124 were able to affect cell viability in various tumor cell lines. In the second part of this work, Inhibitors of Wnt Production (IWP) compounds were, for the first time, characterized as CK1δ inhibitors. IWPs share structural similarities with CK1 inhibitors, so it was hypothesized that they could inhibit CK1 isoforms. Commercially-available IWP inhibited the activity of CK1δ/ε. Interestingly, IWPs potently inhibit the gatekeeper mutant CK1δM82F. In vitro and in silico data revealed that IWPs act in an ATP-competitive manner, binding to the kinase’s ATP pocket and establishing interactions with the gatekeeper residue. IWP-2 was assayed in a panel of 321 eukaryotic kinases, revealing a high specificity towards CK1δ. IWP-4 was found to be a powerful inhibitor of cell proliferation in various cancer cell lines. Also, IWP-2 and IWP-2-V2 were used as scaffolds for further drug design, towards improving their ability to inhibit CK1δ. This was partially accomplished with Compound 17, a novel derivative of IWP-2 obtained with the collaboration of our research partners. Compound 17 showed moderately better IC50 values in comparison with its leading compound while retaining its specificity. These results put into a new perspective the use of IWPs in research since they suggest that the direct effects of IWPs on the Wnt pathway are not limited to the inhibition of Porcupine, but also affect pathways directly related to CK1. Studying inhibitor compounds provides new insights into the mechanisms of kinase activity and highlights the potential of small molecule inhibitors for future drug development.dc.description.abstract
Languageendc.language.iso
PublisherUniversität Ulmdc.publisher
LicenseStandarddc.rights
Link to license texthttps://oparu.uni-ulm.de/xmlui/license_v3dc.rights.uri
KeywordCasein Kinase 1dc.subject
KeywordKinase Inhibitiondc.subject
KeywordIWP-2dc.subject
KeywordPhosphorylationdc.subject
KeywordInhibitor of Wnt Productiondc.subject
KeywordSmall molecule inhibitordc.subject
Dewey Decimal GroupDDC 570 / Life sciencesdc.subject.ddc
Dewey Decimal GroupDDC 610 / Medicine & healthdc.subject.ddc
MeSHCasein kinasesdc.subject.mesh
MeSHProtein kinase inhibitorsdc.subject.mesh
MeSHWnt proteinsdc.subject.mesh
MeSHProtein kinasesdc.subject.mesh
MeSHCasein kinase Idc.subject.mesh
TitleValidation of new Casein Kinase 1 (CK1) small molecule inhibitor compounds and characterization of Inhibitors of Wnt Production (IWPs) as inhibitors of CK1δdc.title
Resource typeDissertationdc.type
Date of acceptance2017-05-05dcterms.dateAccepted
RefereeKnippschild, Uwedc.contributor.referee
RefereeBurster, Timodc.contributor.referee
DOIhttp://dx.doi.org/10.18725/OPARU-5420dc.identifier.doi
PPN1013674502dc.identifier.ppn
URNhttp://nbn-resolving.de/urn:nbn:de:bsz:289-oparu-5477-9dc.identifier.urn
GNDProteinkinase CK1dc.subject.gnd
GNDPhosphorylierungdc.subject.gnd
FacultyMedizinische Fakultätuulm.affiliationGeneral
InstitutionUKU. Klinik für Allgemein- und Viszeralchirurgieuulm.affiliationSpecific
InstitutionUKU. Klinik für Neurochirurgieuulm.affiliationSpecific
Grantor of degreeMedizinische Fakultätuulm.thesisGrantor
DCMI TypeTextuulm.typeDCMI
CategoryPublikationenuulm.category


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