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Covalent‐Allosteric Kinase Inhibitors |
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| Authors: | Jörn Weisner Dr. Rajesh Gontla Leandi van der Westhuizen Sebastian Oeck Julia Ketzer Dr. Petra Janning Dr. André Richters Dr. Thomas Mühlenberg Dr. Zhizhou Fang Dr. Abu Taher Prof. Dr. Verena Jendrossek Dr. Stephen C. Pelly Prof. Dr. Sebastian Bauer Prof. Dr. Willem A. L. van Otterlo Prof. Dr. Daniel Rauh |
| Affiliation: | 1. Technische Universit?t Dortmund, Fakult?t für Chemie und Chemische Biologie, Otto‐Hahn‐Strasse 6, 44227 Dortmund (Germany);2. Department of Chemistry and Polymer Sciences, Stellenbosch University, Matieland (South Africa);3. Institute of Cell Biology (Cancer Research), Department of Molecular Cell Biology, University of Duisburg–Essen, Medical School (Germany);4. Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg–Essen, Medical School (Germany);5. German Cancer Consortium (DKTK), Heidelberg (Germany);6. Max‐Planck‐Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Dortmund (Germany) |
| Abstract: | Targeting and stabilizing distinct kinase conformations is an instrumental strategy for dissecting conformation‐dependent signaling of protein kinases. Herein the structure‐based design, synthesis, and evaluation of pleckstrin homology (PH) domain‐dependent covalent‐allosteric inhibitors (CAIs) of the kinase Akt is reported. These inhibitors bind covalently to a distinct cysteine of the kinase and thereby stabilize the inactive kinase conformation. These modulators exhibit high potency and selectivity, and represent an innovative approach for chemical biology and medicinal chemistry research. |
| Keywords: | cancer drug design inter‐domain interactions medicinal chemistry tumor thermapeutics |