Discovery of selective TYK2 inhibitors: Design, synthesis, in vitro and in silico studies of promising hits with triazolopyrimidinone scaffold

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dc.authoridistanbullu, huseyin/0000-0002-0102-4181
dc.authoridCoban, Gunes/0000-0003-4512-4392
dc.contributor.authorIstanbullu, Huseyin
dc.contributor.authorCoban, Gunes
dc.contributor.authorTurunc, Ezgi
dc.contributor.authorDisel, Cagla
dc.contributor.authorButuner, Bilge Debelec
dc.date.accessioned2024-08-31T07:49:28Z
dc.date.available2024-08-31T07:49:28Z
dc.date.issued2024
dc.departmentEge Üniversitesien_US
dc.description.abstractThe Janus kinase (JAK) -signal transducer and activator of transcription (STAT) pathway mediates many cytokine and growth factor signals. Tyrosine kinase 2 (TYK2), one of the members of this pathway and the first described member of the JAK family. TYK2 associates with inflammatory and autoimmune diseases, cancer and diabetes. Here, we present novel compounds as selective inhibitors of the canonical kinase domain of TYK2 enzyme. These compounds were rationally designed and synthesized with appropriate reactions. Molecular modeling techniques were used to design and optimize the candidates for TYK2 inhibition and to determine the estimated binding orientations of them inside JAKs. Designed compounds potently inhibited TYK2 with good selectivity against other JAKs as determined by in vitro assays. In order to verify its selectivity properties, compound A8 was tested against 58 human kinases (KinaseProfilerTM assay). The effects of the selected seven compounds on the protein levels of members of the JAK/STAT family were also detected in THP-1 monocytes although the basal level of these proteins is poorly detectable. Therefore, their expression was induced by lipopolysaccharide treatment and compounds A8, A15, A18, and A19 were found to be potent inhibitors of the TYK2 enzyme, (9.7 nM, 6.0 nM, 5.0 nM and 10.3 nM, respectively), and have high selectivity index for the JAK1, JAK2, and JAK3 enzymes. These findings suggest that triazolo[1,5-a]pyrimidinone derivatives may be lead compounds for developing potent TYK2-selective inhibitors targeting enzymes' active site.en_US
dc.description.sponsorshipScientific and Techno- logical Research Council of Turkey (TUBITAK) [KBAG-115-Z- 127, SBAG-323-S-003]; Izmir Katip Celebi University Scientific Research Projects Coordination Unit [2018-ONAP- ECZF-0007]en_US
dc.description.sponsorshipThe authors extend their appreciation to the Scientific and Techno- logical Research Council of Turkey (TUBITAK) (project no: KBAG-115-Z- 127 and project no: SBAG-323-S-003) and Izmir Katip Celebi University Scientific Research Projects Coordination Unit (grant no: 2018-ONAP- ECZF-0007) . Additionally, the authors would like to thank Dr. Cigdem Selli (University of Edinburgh Cancer Research Centre) for her contri- butions to the development of the study idea.en_US
dc.identifier.doi10.1016/j.bioorg.2024.107430
dc.identifier.issn0045-2068
dc.identifier.issn1090-2120
dc.identifier.pmid38728909en_US
dc.identifier.scopus2-s2.0-85193942244en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.1016/j.bioorg.2024.107430
dc.identifier.urihttps://hdl.handle.net/11454/104883
dc.identifier.volume148en_US
dc.identifier.wosWOS:001240339800001en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherAcademic Press Inc Elsevier Scienceen_US
dc.relation.ispartofBioorganic Chemistryen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.snmz20240831_Uen_US
dc.subjectJak/Staten_US
dc.subjectTyk2en_US
dc.subjectJh1en_US
dc.subjectTriazolopyrimidinoneen_US
dc.subjectAutoimmuneen_US
dc.titleDiscovery of selective TYK2 inhibitors: Design, synthesis, in vitro and in silico studies of promising hits with triazolopyrimidinone scaffolden_US
dc.typeArticleen_US

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