A Three-Hybrid Approach to Scanning the Proteome for Targets of Small Molecule Kinase Inhibitors

Becker, Frank; Murthi, Krishna K.; Smith, Chase C.; Come, Jon H.; Costa-Roldán, Nuria; Kaufmann, Christine; Hanke, Urs; Degenhart, Carsten; Baumann, Sabine W.; Wallner, Wolfgang; Huber, Andrea; Dédier, Séverine; Dill, Simone; Kinsman, David; Hediger, Mark; Bockovich, Nicholas; Meier‐Ewert, Sebastian; Kluge, Arthur F.; Kley, Nikolai

doi:10.1016/j.chembiol.2004.02.001

Cited by 123 publications

(95 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…For example, the yeast three-hybrid approach has generated new insight into the selectivity of cyclin-dependent kinase (CDK) inhibitors [19]. In this case, the compounds were covalently attached to the dihydrofolate reductase (DHFR) inhibitor methotrexate via a PEG spacer.…”

Section: Microarrays Miniaturisation and Proteomic Methodsmentioning

confidence: 99%

Measuring and interpreting the selectivity of protein kinase inhibitors

2009

View full text Add to dashboard Cite

Protein kinase inhibitors are a well-established class of clinically useful drugs, particularly for the treatment of cancer. Achieving inhibitor selectivity for particular protein kinases often remains a significant challenge in the development of new small molecules as drugs or as tools for chemical biology research. This review summarises the methodologies available for measuring kinase inhibitor selectivity, both in vitro and in cells. The interpretation of kinase inhibitor selectivity data is discussed, particularly with reference to the structural biology of the protein targets. Measurement and prediction of kinase inhibitor selectivity will be important for the development of new multi-targeted kinase inhibitors.

show abstract

Section: Microarrays Miniaturisation and Proteomic Methodsmentioning

confidence: 99%

Measuring and interpreting the selectivity of protein kinase inhibitors

2009

View full text Add to dashboard Cite

show abstract

“…Its selectivity has been extensively studied using either panels of purified kinases (z152 kinases tested; refs. 23 -25), affinity chromatography on immobilized roscovitine (25,26), a quantitative competition assay (27), and a yeast three-hybrid screen (28). Altogether, these methods have provided a rather precise view on the targets of (R)-roscovitine.…”

Section: Introductionmentioning

confidence: 99%

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

Bettayeb

Sallam

Ferandin

et al. 2008

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

show abstract

“…25 although we currently have no evidence for an interaction of c-yes with purvalanol a, it is conceivable that c-yes expressed in yeast is a target of purvalanol a, thereby leading to the recovery of c-yesinduced inhibition of the yeast growth. these findings indicate that the actions of the 6 compounds are exerted through c-yes rather than nonspecific off-targets, thus supporting the validity of the system.…”

Section: Figmentioning

confidence: 99%

Comprehensive Screening of Human Genes with Inhibitory Effects on Yeast Growth and Validation of a Yeast Cell-Based System for Screening Chemicals

et al. 2010

View full text Add to dashboard Cite

To evaluate yeast as a high-throughput cell-based system for screening chemicals that may lead to drug development, 10,302 full-length human cDNAs (~50% of the total cDNAs) were introduced into yeast. Approximately 5.6% (583 clones) of the cDNAs repressed the growth of yeast. Notably, ~25% of the repressive cDNAs encoded uncharacterized proteins. Small chemicals can be readily surveyed by monitoring their restorative effects on the growth of yeast. The authors focused on protein kinases because protein kinases are involved in various diseases. Among 263 protein kinase cDNAs (~50% of the total) expressed in yeast, 60 cDNAs (~23%), including c-Yes, a member of the Src tyrosine kinase family, inhibited the growth of yeast. Known inhibitors for protein kinases were examined for whether they reversed the c-Yes-induced inhibition of the yeast growth. Among 85 inhibitors tested, 6 compounds (PP2, PP1, SU6656, purvalanol, radicicol, and geldanamycin) reversed the inhibition, indicating a high specificity sufficient for validating this screening system. Human c-Yes was found to interact with Hsc82, one of the yeast chaperones. Radicicol and geldanamycin probably exerted their actions through interactions with Hsc82. These results indicate that when human proteins requiring molecular chaperones for their activities are subjected to the yeast screening system, 2 groups of chemicals may be found. The actions of one group are exerted through direct interactions with the human proteins, whereas those of the other group are mediated through interactions with chaperones.

show abstract

A Three-Hybrid Approach to Scanning the Proteome for Targets of Small Molecule Kinase Inhibitors

Cited by 123 publications

References 41 publications

Measuring and interpreting the selectivity of protein kinase inhibitors

Measuring and interpreting the selectivity of protein kinase inhibitors

N-&-N, a new class of cell death-inducing kinase inhibitors derived from the purine roscovitine

Comprehensive Screening of Human Genes with Inhibitory Effects on Yeast Growth and Validation of a Yeast Cell-Based System for Screening Chemicals

Contact Info

Product

Resources

About