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dc.contributor.authorKleiner, Ralph Elliot
dc.contributor.authorDumelin, Christoph
dc.contributor.authorTiu, Gerald C.
dc.contributor.authorSakurai, Kaori
dc.contributor.authorLiu, David Ruchien
dc.date.accessioned2013-10-25T12:19:21Z
dc.date.issued2010
dc.identifier.citationKleiner, Ralph E., Christoph E. Dumelin, Gerald C. Tiu, Kaori Sakurai, and David R. Liu. 2010. In Vitro Selection of a DNA-Templated Small-Molecule Library Reveals a Class of Macrocyclic Kinase Inhibitors. Journal of the American Chemical Society 132(33): 11779-11791.en_US
dc.identifier.issn0002-7863en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11213322
dc.description.abstractDNA-templated organic synthesis enables the translation of DNA sequences into synthetic small-molecule libraries suitable for in vitro selection. Previously, we described the DNA-templated multistep synthesis of a 13 824-membered small-molecule macrocycle library. Here, we report the discovery of small molecules that modulate the activity of kinase enzymes through the in vitro selection of this DNA-templated small-molecule macrocycle library against 36 biomedically relevant protein targets. DNA encoding selection survivors was amplified by PCR and identified by ultra-high-throughput DNA sequencing. Macrocycles corresponding to DNA sequences enriched upon selection against several protein kinases were synthesized on a multimilligram scale. In vitro assays revealed that these macrocycles inhibit (or activate) the kinases against which they were selected with IC50 values as low as 680 nM. We characterized in depth a family of macrocycles enriched upon selection against Src kinase, and showed that inhibition was highly dependent on the identity of macrocycle building blocks as well as on backbone conformation. Two macrocycles in this family exhibited unusually strong Src inhibition selectivity even among kinases closely related to Src. One macrocycle was found to activate, rather than inhibit, its target kinase, VEGFR2. Taken together, these results establish the use of DNA-templated synthesis and in vitro selection to discover small molecules that modulate enzyme activities, and also reveal a new scaffold for selective ATP-competitive kinase inhibition.en_US
dc.description.sponsorshipChemistry and Chemical Biologyen_US
dc.language.isoen_USen_US
dc.publisherAmerican Chemical Societyen_US
dc.relation.isversionofdoi:10.1021/ja104903xen_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2924185/pdf/en_US
dash.licenseLAA
dc.titleIn Vitro Selection of a DNA-Templated Small-Molecule Library Reveals a Class of Macrocyclic Kinase Inhibitorsen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalJournal of the American Chemical Societyen_US
dash.depositing.authorLiu, David Ruchien
dc.date.available2013-10-25T12:19:21Z
dash.affiliation.otherFAS^FCOR^CCB - Grad Stipendsen_US
dash.affiliation.otherFAS^FCOR^CCB - TF/TAen_US
dash.affiliation.otherFAS^FCOR^CCB - Sr. Facultyen_US
dash.affiliation.otherFAS^FCOR^CCB - Other Academicen_US
dc.identifier.doi10.1021/ja104903x*
dash.contributor.affiliatedDumelin, Christoph
dash.contributor.affiliatedKleiner, Ralph
dash.contributor.affiliatedLiu, David


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