Covalent‐Allosteric Kinase Inhibitors1. Issue 35 (25th June 2015)

• Record Type: Journal Article
• Authors: Weisner, Jörn; Gontla, Rajesh; van der Westhuizen, Leandi; Oeck, Sebastian; Ketzer, Julia; Janning, Petra; Richters, André; Mühlenberg, Thomas; Fang, Zhizhou; Taher, Abu; Jendrossek, Verena; Pelly, Stephen C.; Bauer, Sebastian; van Otterlo, Willem A. L.; Rauh, Daniel
• Is Part Of: Angewandte Chemie international edition. Volume 54:Issue 35(2015)
• Page Start: 10313
• Page End: 10316
• Publication Date: 2015-06-25
• Subjects: Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201502142
• Languages: English
• ISSNs: 1433-7851

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>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.</p> </abstract>