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Covalent‐Allosteric Inhibitors to Achieve Akt Isoform‐Selectivity
Author(s) -
Quambusch Lena,
Landel Ina,
Depta Laura,
Weisner Jörn,
Uhlenbrock Niklas,
Müller Matthias P.,
Glanemann Franziska,
Althoff Kristina,
Siveke Jens T.,
Rauh Daniel
Publication year - 2019
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201909857
Subject(s) - allosteric regulation , gene isoform , protein kinase b , chemistry , biochemistry , small molecule , covalent bond , kinase , enzyme , microbiology and biotechnology , signal transduction , biology , gene , organic chemistry
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.