Saturday, October 5, 2019

Covalent‐Allosteric Inhibitors to Achieve Akt Isoform‐Selectivity

Quambusch, L. , Landel, I. , Depta, L. , Weisner, J. , Uhlenbrock, N. , Müller, M. P., Glanemann, F. , Althoff, K. , Siveke, J. T. and Rauh, D.

Angew. Chem. Int. Ed., 2019

doi: 10.1002/anie.201909857

Isoforms of protein kinase Akt (Akt1/2/3) are involved in a myriad of 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. Here, 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 first set of isoform‐selective covalent‐allosteric Akt inhibitors that emerged from this approach showed a conclusive structure‐activity relationship and broke ground for further structure‐guided development of selective probes to delineate the isoform‐specific functions of Akt kinases.

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1

Adrian Hall, Jan Abendroth, Madison J. Bolejack, Tom Ceska, Sylvie Dell’Aiera, Victoria Ellis, David Fox, Cyril François, Muigai M. Muruthi,...