Covalent-allosteric inhibitors to achieve akt isoform-selectivity

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dc.contributor.authorQuambusch, Lena
dc.contributor.authorLandel, Ina
dc.contributor.authorDepta, Laura
dc.contributor.authorWeisner, Jörn
dc.contributor.authorUhlenbrock, Niklas
dc.contributor.authorMüller, Matthias P.
dc.contributor.authorGlanemann, Franziska
dc.contributor.authorAlthoff, Kristina
dc.contributor.authorSiveke, Jens T.
dc.contributor.authorRauh, Daniel
dc.date.accessioned2020-03-05T13:19:32Z
dc.date.available2020-03-05T13:19:32Z
dc.date.issued2019-10-04
dc.description.abstractIsoforms of protein kinase Akt are involved in essential processes including cell proliferation, survival, and metabolism. However, their individual roles in health and disease have not been thoroughly evaluated. Thus, there is an urgent need for perturbation studies, preferably mediated by highly selective bioactive small molecules. Herein, we present a structure‐guided approach for the design of structurally diverse and pharmacologically beneficial covalent‐allosteric modifiers, which enabled an investigation of the isoform‐specific preferences and the important residues within the allosteric site of the different isoforms. The biochemical, cellular, and structural evaluations revealed interactions responsible for the selective binding profiles. The isoform‐selective covalent‐allosteric Akt inhibitors that emerged from this approach showed a conclusive structure–activity relationship and broke ground in the development of selective probes to delineate the isoform‐specific functions of Akt kinases.en
dc.identifier.urihttp://hdl.handle.net/2003/39033
dc.identifier.urihttp://dx.doi.org/10.17877/DE290R-20952
dc.language.isoende
dc.relation.ispartofseriesAngewandte Chemie International Edition;Vol. 58, Issue 52, 18823-18829
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectAkt isoformsen
dc.subjectAllosteric sitesen
dc.subjectCanceren
dc.subjectCovalent inhibitorsen
dc.subjectIsoform selectivityen
dc.subject.ddc570
dc.subject.ddc540
dc.titleCovalent-allosteric inhibitors to achieve akt isoform-selectivityen
dc.typeTextde
dc.type.publicationtypearticlede
dcterms.accessRightsopen access
eldorado.secondarypublicationtruede
eldorado.secondarypublication.primarycitationAngewandte Chemie International Edition. Vol. 58, 2019, Issue 52, 8823 –18829de
eldorado.secondarypublication.primaryidentifierhttps://doi.org/10.1002/anie.201909857de

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