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Angew Chem Int Ed Engl. 2015 Aug 24;54(35):10313-6. doi: 10.1002/anie.201502142. Epub 2015 Jun 25.

Covalent-Allosteric Kinase Inhibitors.

Author information

1
Technische Universität Dortmund, Fakultät 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).
7
Technische Universität Dortmund, Fakultät für Chemie und Chemische Biologie, Otto-Hahn-Strasse 6, 44227 Dortmund (Germany). daniel.rauh@tu-dortmund.de.

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

PMID:
26110718
DOI:
10.1002/anie.201502142
[Indexed for MEDLINE]

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