The First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activities

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dc.contributor.authorCiftci, Halil Ibrahim
dc.contributor.authorOzturk, Safiye Emirdag
dc.contributor.authorAli, Taha F. S.
dc.contributor.authorRadwan, Mohamed O.
dc.contributor.authorTateishi, Hiroshi
dc.contributor.authorKoga, Ryoko
dc.contributor.authorOcak, Zeynep
dc.contributor.authorCan, Mustafa
dc.contributor.authorOtsuka, Masami
dc.contributor.authorFujita, Mikako
dc.date.accessioned2019-10-27T10:07:21Z
dc.date.available2019-10-27T10:07:21Z
dc.date.issued2018
dc.departmentEge Üniversitesien_US
dc.description.abstractThe discovery of the chimeric tyrosine kinase breakpoint cluster region kinase-Abelson kinase (BCR-ABL)-targeted drug imatinib conceptually changed the treatment of chronic myelogenous leukemia (CML). However, some CML patients show drug resistance to imatinib. To address this issue, some artificial heterocyclic compounds have been identified as BCR-ABL inhibitors. Here we examined whether plant-derived pentacyclic triterpenoid gypsogenin and/or their derivatives show inhibitory activity against BCR-ABL. Among the three derivatives, benzyl 3-hydroxy-23-oxoolean-12-en-28-oate (1c) was found to be the most effective anticancer agent on the CML cell line K562, with an IC50 value of 9.3 mu m. In contrast, the IC50 against normal peripheral blood mononuclear cells was 276.0 mu m, showing better selectivity than imatinib. Compound 1c had in vitro inhibitory activity against Abelson kinase 1 (ABLI) (IC50=8.7 mu m), the kinase component of BCR-ABL. In addition, compound 1c showed a different inhibitory profile against eight kinases compared with imatinib. The interaction between ATP binding site of ABL and lc was examined by molecular docking study, and the binding mode was different from imatinib and newer generation inhibitors. Furthermore, 1c suppressed signaling downstream of BCR-ABL. This study suggests the possibility that plant extracts may be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR-ABL inhibitors.en_US
dc.description.sponsorshipJapan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [17H03999]en_US
dc.description.sponsorshipThis work was supported in part by a Grant-in-Aid for Scientific Research (B) from the Japan Society for the Promotion of Science (17H03999) (to M. O.).en_US
dc.identifier.endpage574en_US
dc.identifier.issn0918-6158
dc.identifier.issue4en_US
dc.identifier.pmid29386476en_US
dc.identifier.scopusqualityN/Aen_US
dc.identifier.startpage570en_US
dc.identifier.urihttps://hdl.handle.net/11454/30545
dc.identifier.volume41en_US
dc.identifier.wosWOS:000429294400015en_US
dc.identifier.wosqualityN/Aen_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherPharmaceutical Soc Japanen_US
dc.relation.ispartofBiological & Pharmaceutical Bulletinen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectgypsogeninen_US
dc.subjectAbelson tyrosine-protein kinase 1en_US
dc.subjectchronic myelogenous leukemiaen_US
dc.titleThe First Pentacyclic Triterpenoid Gypsogenin Derivative Exhibiting Anti-ABL1 Kinase and Anti-chronic Myelogenous Leukemia Activitiesen_US
dc.typeArticleen_US

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