%0 Journal Article %1 C8SC05212C %A Uhlenbrock, Niklas %A Smith, Steven %A Weisner, Jörn %A Landel, Ina %A Lindemann, Marius %A Le, Thien Anh %A Hardick, Julia %A Gontla, Rajesh %A Scheinpflug, Rebekka %A Czodrowski, Paul %A Janning, Petra %A Depta, Laura %A Quambusch, Lena %A Müller, Matthias P. %A Engels, Bernd %A Rauh, Daniel %D 2019 %I The Royal Society of Chemistry %J Chem. Sci. %K Engels myown %P - %R 10.1039/C8SC05212C %T Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt %U http://dx.doi.org/10.1039/C8SC05212C %X The Ser/Thr kinase Akt (Protein Kinase B/PKB) is a master switch in cellular signal transduction pathways. Its downstream signaling influences cell proliferation, cell growth, and apoptosis, rendering Akt a prominent drug target. The unique activation mechanism of Akt involves a change of the relative orientation of its N-terminal pleckstrin homology (PH) and the kinase domain and makes this kinase suitable for highly specific allosteric modulation. Here we present a unique set of crystal structures of covalent-allosteric interdomain inhibitors in complex with full-length Akt and report the structure-based design, synthesis, biological and pharmacological evaluation of a focused library of these innovative inhibitors.

@article{C8SC05212C, abstract = {The Ser/Thr kinase Akt (Protein Kinase B/PKB) is a master switch in cellular signal transduction pathways. Its downstream signaling influences cell proliferation{,} cell growth{,} and apoptosis{,} rendering Akt a prominent drug target. The unique activation mechanism of Akt involves a change of the relative orientation of its N-terminal pleckstrin homology (PH) and the kinase domain and makes this kinase suitable for highly specific allosteric modulation. Here we present a unique set of crystal structures of covalent-allosteric interdomain inhibitors in complex with full-length Akt and report the structure-based design{,} synthesis{,} biological and pharmacological evaluation of a focused library of these innovative inhibitors.}, added-at = {2019-02-25T18:41:52.000+0100}, author = {Uhlenbrock, Niklas and Smith, Steven and Weisner, Jörn and Landel, Ina and Lindemann, Marius and Le, Thien Anh and Hardick, Julia and Gontla, Rajesh and Scheinpflug, Rebekka and Czodrowski, Paul and Janning, Petra and Depta, Laura and Quambusch, Lena and Müller, Matthias P. and Engels, Bernd and Rauh, Daniel}, biburl = {https://www.bibsonomy.org/bibtex/2107699e3e655c75acde3b5b4c523a2d4/akengels}, doi = {10.1039/C8SC05212C}, interhash = {20c588de2edc394345d23b6861004681}, intrahash = {107699e3e655c75acde3b5b4c523a2d4}, journal = {Chem. Sci.}, keywords = {Engels myown}, pages = {-}, publisher = {The Royal Society of Chemistry}, timestamp = {2020-06-21T07:16:52.000+0200}, title = {Structural and chemical insights into the covalent-allosteric inhibition of the protein kinase Akt}, url = {http://dx.doi.org/10.1039/C8SC05212C}, year = 2019 }