Universität zu Köln

Fang, Zhizhou, Simard, Jeffrey R., Plenker, Dennis, Nguyen, Hoang D., Wolle, Patrik, Baumeister, Stefan and Rauh, Daniel ORCID: 0000-0002-1970-7642 (2015). Discovery of Inter-Domain Stabilizers-A Novel Assay System for Allosteric Akt Inhibitors. ACS Chem. Biol., 10 (1). S. 279 - 289. WASHINGTON: AMER CHEMICAL SOC. ISSN 1554-8937

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Abstract

In addition to the catalytically active kinase domain, most kinases feature regulatory domains that govern their activity. Modulating and interfering with these interdomain interactions presents a major opportunity for understanding biological systems and developing novel therapeutics. Therefore, small molecule inhibitors that target these interactions through an allosteric mode of action have high intrinsic selectivity, as these interactions are often unique to a single kinase or kinase family. Here we report the development of iFLiK (interface-Fluorescent Labels in Kinases), a fluorescence-based assay that can monitor such interdomain interactions. Using iFLiK, we have demonstrated selective detection of allosteric Akt inhibitors that induce an inactive closed conformation unique to Akt. This methodology easily distinguished small molecule allosteric inhibitors from classic ATP-competitive inhibitors. Screening an in-house compound library with iFLiK, we were able to identify novel compounds with a scaffold that has not been previously described for allosteric Akt inhibitors.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Fang, Zhizhou UNSPECIFIED UNSPECIFIED UNSPECIFIED Simard, Jeffrey R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Plenker, Dennis UNSPECIFIED UNSPECIFIED UNSPECIFIED Nguyen, Hoang D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wolle, Patrik UNSPECIFIED UNSPECIFIED UNSPECIFIED Baumeister, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Rauh, Daniel UNSPECIFIED orcid.org/0000-0002-1970-7642 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-417519
DOI:	10.1021/cb500355c
Journal or Publication Title:	ACS Chem. Biol.
Volume:	10
Number:	1
Page Range:	S. 279 - 289
Date:	2015
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
ISSN:	1554-8937
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language PROTEIN-KINASE-B; SCREENING ASSAY; FLUORESCENCE; PATHWAY; POTENT; CELLS; IDENTIFICATION; MUTATION; TARGET Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/41751