Covalent‐Allosteric Inhibitors to Achieve Akt Isoform‐Selectivity. Issue 52 (8th November 2019)

• Record Type: Journal Article
• Authors: Quambusch, Lena; Landel, Ina; Depta, Laura; Weisner, Jörn; Uhlenbrock, Niklas; Müller, Matthias P.; Glanemann, Franziska; Althoff, Kristina; Siveke, Jens T.; Rauh, Daniel
• Is Part Of: Angewandte Chemie international edition. Volume 58:Issue 52(2019)
• Page Start: 18823
• Page End: 18829
• Publication Date: 2019-11-08
• Subjects: Akt isoforms -- allosteric sites -- cancer -- covalent inhibitors -- isoform selectivity; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201909857
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: 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. Abstract : Akt now ! A structure and homology model guided approach for the design of diverse and pharmacologically beneficial covalent‐allosteric modifiers for protein kinase Akt is presented. The isoform‐selective Akt inhibitors show a conclusive structure–activity relationship and break ground for further development of selective probes for the dissection of Akt isoform‐specific functions.