title: Covalent-Allosteric Kinase Inhibitors.
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.
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
authors.forename: Jörn
authors.initials: J
authors.lastname: Weisner
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
authors.forename: Rajesh
authors.initials: R
authors.lastname: Gontla
authors.affiliation: Department of Chemistry and Polymer Sciences, Stellenbosch University, Matieland (South Africa).
authors.forename: Leandi
authors.initials: L
authors.lastname: van der Westhuizen
authors.affiliation: Institute of Cell Biology (Cancer Research), Department of Molecular Cell Biology, University of Duisburg-Essen, Medical School (Germany).
authors.forename: Sebastian
authors.initials: S
authors.lastname: Oeck
authors.affiliation: Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School (Germany).|German Cancer Consortium (DKTK), Heidelberg (Germany).
authors.forename: Julia
authors.initials: J
authors.lastname: Ketzer
authors.affiliation: Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, Dortmund (Germany).
authors.forename: Petra
authors.initials: P
authors.lastname: Janning
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
authors.forename: André
authors.initials: A
authors.lastname: Richters
authors.affiliation: Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School (Germany).|German Cancer Consortium (DKTK), Heidelberg (Germany).
authors.forename: Thomas
authors.initials: T
authors.lastname: Mühlenberg
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany).
authors.forename: Zhizhou
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Chemistry and Polymer Sciences, Stellenbosch University, Matieland (South Africa).
authors.forename: Abu
authors.initials: A
authors.lastname: Taher
authors.affiliation: Institute of Cell Biology (Cancer Research), Department of Molecular Cell Biology, University of Duisburg-Essen, Medical School (Germany).
authors.forename: Verena
authors.initials: V
authors.lastname: Jendrossek
authors.affiliation: Department of Chemistry and Polymer Sciences, Stellenbosch University, Matieland (South Africa).
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Pelly
authors.affiliation: Department of Medical Oncology, Sarcoma Center, West German Cancer Center, University Duisburg-Essen, Medical School (Germany).|German Cancer Consortium (DKTK), Heidelberg (Germany).
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bauer
authors.affiliation: Department of Chemistry and Polymer Sciences, Stellenbosch University, Matieland (South Africa).
authors.forename: Willem A L
authors.initials: WA
authors.lastname: van Otterlo
authors.affiliation: Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany). daniel.rauh@tu-dortmund.de.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauh
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000494:Allosteric Regulation; D001667:Binding, Competitive; D006801:Humans; D008958:Models, Molecular; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D047428:Protein Kinase Inhibitors; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt
keywords: cancer; drug design; inter-domain interactions; medicinal chemistry; tumor thermapeutics