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Novel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1

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dc.contributor.author심태보-
dc.date.accessioned2022-03-11T06:16:46Z-
dc.date.available2022-03-11T06:16:46Z-
dc.date.issued2022-01-
dc.identifier.issn0022-2623-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/188018-
dc.description.abstractThe polo-box domain (PBD) of Plk1 is a promising target for cancer therapeutics. We designed and synthesized novel phosphorylated macrocyclic peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL. The inhibitory activities of 16e on Plk1-PBD is >30-fold higher than those of PMQSpTPL. Both 16a and 16e possess excellent selectivity for Plk1-PBD over Plk2/3-PBD. Analysis of the cocrystal structure of Plk1-PBD in complex with 16a reveals that the 3-(trifluoromethyl)benzoyl group in 16a interacts with Arg516 through a π-stacking interaction. This π-stacking interaction, which has not been reported previously, provides insight into the design of novel and potent Plk1-PBD inhibitors. Furthermore, 16h, a PEGlyated macrocyclic phosphopeptide derivative, induces Plk1 delocalization and mitotic failure in HeLa cells. Also, the number of phospho-H3-positive cells in a zebrafish embryo increases in proportion to the amount of 16a. Collectively, the novel macrocyclic peptidomimetics should serve as valuable templates for the design of potent and novel Plk1-PBD inhibitors.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherAmerican Chemical Society-
dc.relation.isPartOfJOURNAL OF MEDICINAL CHEMISTRY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.subject.MESHAnimals-
dc.subject.MESHCell Cycle Proteins / antagonists & inhibitors*-
dc.subject.MESHCell Cycle Proteins / chemistry-
dc.subject.MESHCell Cycle Proteins / metabolism-
dc.subject.MESHHEK293 Cells-
dc.subject.MESHHeLa Cells-
dc.subject.MESHHumans-
dc.subject.MESHMolecular Docking Simulation-
dc.subject.MESHMolecular Structure-
dc.subject.MESHPeptides, Cyclic / chemical synthesis-
dc.subject.MESHPeptides, Cyclic / metabolism-
dc.subject.MESHPeptides, Cyclic / pharmacology*-
dc.subject.MESHPeptidomimetics / chemical synthesis-
dc.subject.MESHPeptidomimetics / metabolism-
dc.subject.MESHPeptidomimetics / pharmacology*-
dc.subject.MESHProtein Binding-
dc.subject.MESHProtein Domains-
dc.subject.MESHProtein Kinase Inhibitors / chemical synthesis-
dc.subject.MESHProtein Kinase Inhibitors / metabolism-
dc.subject.MESHProtein Kinase Inhibitors / pharmacology*-
dc.subject.MESHProtein Serine-Threonine Kinases / antagonists & inhibitors*-
dc.subject.MESHProtein Serine-Threonine Kinases / chemistry-
dc.subject.MESHProtein Serine-Threonine Kinases / metabolism-
dc.subject.MESHProto-Oncogene Proteins / antagonists & inhibitors*-
dc.subject.MESHProto-Oncogene Proteins / chemistry-
dc.subject.MESHProto-Oncogene Proteins / metabolism-
dc.subject.MESHStructure-Activity Relationship-
dc.subject.MESHZebrafish-
dc.titleNovel Macrocyclic Peptidomimetics Targeting the Polo-Box Domain of Polo-Like Kinase 1-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentBioMedical Science Institute (의생명과학부)-
dc.contributor.googleauthorSeongShick Ryu-
dc.contributor.googleauthorJung-Eun Park-
dc.contributor.googleauthorYoung Jin Ham-
dc.contributor.googleauthorDaniel C Lim-
dc.contributor.googleauthorNicholas P Kwiatkowski-
dc.contributor.googleauthorDo-Hee Kim-
dc.contributor.googleauthorDebabrata Bhunia-
dc.contributor.googleauthorNam Doo Kim-
dc.contributor.googleauthorMichael B Yaffe-
dc.contributor.googleauthorWoolim Son-
dc.contributor.googleauthorNamkyoung Kim-
dc.contributor.googleauthorTae-Ik Choi-
dc.contributor.googleauthorPuspanjali Swain-
dc.contributor.googleauthorCheol-Hee Kim-
dc.contributor.googleauthorJin-Young Lee-
dc.contributor.googleauthorNathanael S Gray-
dc.contributor.googleauthorKyung S Lee-
dc.contributor.googleauthorTaebo Sim-
dc.identifier.doi10.1021/acs.jmedchem.1c01359-
dc.contributor.localIdA05926-
dc.relation.journalcodeJ01588-
dc.identifier.eissn1520-4804-
dc.identifier.pmid35029981-
dc.identifier.urlhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.1c01359-
dc.contributor.alternativeNameSim, Taebo-
dc.contributor.affiliatedAuthor심태보-
dc.citation.volume65-
dc.citation.number3-
dc.citation.startPage1915-
dc.citation.endPage1932-
dc.identifier.bibliographicCitationJOURNAL OF MEDICINAL CHEMISTRY, Vol.65(3) : 1915-1932, 2022-01-
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers

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