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dc.contributor.authorLightfoot, Helenen
dc.contributor.authorMiska, Ericen
dc.contributor.authorBalasubramanian, Shankaren
dc.date.accessioned2016-11-30T16:34:44Z
dc.date.available2016-11-30T16:34:44Z
dc.date.issued2016-11en
dc.identifier.issn1477-0520
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/261365
dc.description.abstractThe protein Lin28 and microRNA let-7 play critical roles in mammalian development and human disease. Lin28 inhibits let-7 biogenesis through direct interaction with let-7 precursors (pre-let-7). Accumulating evidence in vitro and in vivo suggests this interaction plays a dominant role in embryonic stem cell self-renewal and tumorigenesis. Thus the Lin28-let-7 interaction might be an attractive drug target, if not for the well-known difficulties in targeting protein-RNA interactions with drugs. The identification and development of suitable probe molecules to further elucidate therapeutic potential, as well as mechanistic details of this pathway will be valuable. We report the development and application of a biophysical high-throughput screening assay for the identification of small molecule inhibitors of the Lin28-pre-let-7 interaction. A library of pharmacologically active small molecules was screened and several small molecule inhibitors were identified and biochemically validated. Of these four validated inhibitors, two compounds successfully restored processing of pre-let-7g in the presence of Lin28, validating the concept. Thus, we have identified examples of small molecule inhibitors of the interaction between Lin28 and pre-let-7. This study provides a proof of concept for small molecule inhibitors that antagonise the effects of Lin28 and enhance processing of let-7 miRNA.
dc.description.sponsorshipThe authors would like to thank Cancer Research UK for the PhD studentship to HLL and for programme funding to SB and EAM.
dc.format.mediumPrinten
dc.languageengen
dc.publisherRoyal Society of Chemistry
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleIdentification of small molecule inhibitors of the Lin28-mediated blockage of pre-let-7g processing.en
dc.typeArticle
prism.endingPage10216
prism.publicationDate2016en
prism.publicationNameOrganic & biomolecular chemistryen
prism.startingPage10208
prism.volume14en
dc.identifier.doi10.17863/CAM.6535
dcterms.dateAccepted2016-10-04en
rioxxterms.versionofrecord10.1039/c6ob01945een
rioxxterms.versionAMen
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/en
rioxxterms.licenseref.startdate2016-11en
dc.contributor.orcidMiska, Eric [0000-0002-4450-576X]
dc.contributor.orcidBalasubramanian, Shankar [0000-0002-0281-5815]
dc.identifier.eissn1477-0539
rioxxterms.typeJournal Article/Reviewen
rioxxterms.freetoread.startdate2017-10-04


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International