In:
Angewandte Chemie International Edition, Wiley, Vol. 58, No. 52 ( 2019-12-19), p. 18823-18829
Kurzfassung:
Isoforms 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.
Materialart:
Online-Ressource
ISSN:
1433-7851
,
1521-3773
DOI:
10.1002/anie.201909857
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2019
ZDB Id:
2011836-3
ZDB Id:
123227-7
