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Covalent‐Allosteric Kinase Inhibitors
Author(s) -
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
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201502142
Subject(s) - allosteric regulation , pleckstrin homology domain , kinase , chemistry , biochemistry , covalent bond , protein kinase domain , cysteine , transferase , protein kinase b , enzyme , signal transduction , organic chemistry , mutant , gene
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.