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dc.contributor.authorLee, Jae Wook-
dc.contributor.authorHirota, Tsuyoshi-
dc.contributor.authorKumar, Anupriya-
dc.contributor.authorKim, Nam-Jung-
dc.contributor.authorIrle, Stephan-
dc.contributor.authorKay, Steve A.-
dc.date.accessioned2024-01-20T06:04:45Z-
dc.date.available2024-01-20T06:04:45Z-
dc.date.created2021-09-05-
dc.date.issued2015-09-
dc.identifier.issn1860-7179-
dc.identifier.urihttps://pubs.kist.re.kr/handle/201004/125063-
dc.description.abstractSmall-molecule probes have been playing prominent roles in furthering our understanding of the molecular underpinnings of the circadian clock. We previously discovered a carbazole derivative, KL001 (N-(3-(9H-carbazol-9-yl)-2-hydroxypropyl)-N-(furan-2-ylmethyl)methanesulfonamide), as a stabilizer of the clock protein cryptochrome (CRY). Herein we describe an extensive structure-activity relationship analysis of KL001 derivatives leading to the development of a highly active derivative: 2-(9H-carbazol-9-yl)-N-(2-chloro-6-cyanophenyl)acetamide (KL044). Subsequent 3D-QSAR analysis identified critical features of KL001 derivatives and provided a molecular-level understanding of their interaction with CRY. The electron-rich carbazole, amide/hydroxy linker, sulfonyl group, and electron-withdrawing nitrile moieties contribute to greater biological activity. The hydrogen bonding interactions with Ser394 and His357 as well as stronger CH- interactions with Trp290 make KL044 a better binder than KL001. KL044 lengthened the circadian period, repressed Per2 activity, and stabilized CRY in reporter assays with roughly tenfold higher potency than KL001. Altogether, KL044 is a powerful chemical tool to control the function of the circadian clock through its action on CRY.-
dc.languageEnglish-
dc.publisherWILEY-V C H VERLAG GMBH-
dc.subjectDEGRADATION-
dc.subjectREVEALS-
dc.subjectFBXL3-
dc.titleDevelopment of Small-Molecule Cryptochrome Stabilizer Derivatives as Modulators of the Circadian Clock-
dc.typeArticle-
dc.identifier.doi10.1002/cmdc.201500260-
dc.description.journalClass1-
dc.identifier.bibliographicCitationCHEMMEDCHEM, v.10, no.9, pp.1489 - 1497-
dc.citation.titleCHEMMEDCHEM-
dc.citation.volume10-
dc.citation.number9-
dc.citation.startPage1489-
dc.citation.endPage1497-
dc.description.journalRegisteredClassscie-
dc.description.journalRegisteredClassscopus-
dc.identifier.wosid000360499400006-
dc.identifier.scopusid2-s2.0-84940371212-
dc.relation.journalWebOfScienceCategoryChemistry, Medicinal-
dc.relation.journalWebOfScienceCategoryPharmacology & Pharmacy-
dc.relation.journalResearchAreaPharmacology & Pharmacy-
dc.type.docTypeArticle-
dc.subject.keywordPlusDEGRADATION-
dc.subject.keywordPlusREVEALS-
dc.subject.keywordPlusFBXL3-
dc.subject.keywordAuthor3D-QSAR-
dc.subject.keywordAuthorcircadian clock-
dc.subject.keywordAuthorcryptochrome-
dc.subject.keywordAuthorprotein degradation-
dc.subject.keywordAuthorsmall molecule-
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