Oncotarget

Research Papers:

Single Enantiomer of YK-4-279 Demonstrates Specificity in Targeting the Oncogene EWS-FLI1

Julie S. Barber-Rotenberg, Saravana P. Selvanathan, Yali Kong, Hayriye V. Erkizan, Tara M. Snyder, S. Peter Hong, Christina L. Kobs, Natalie L. South, Steven Summer, Philip J. Monroe, Maksymilian Chruszcz, Veselin Dobrev, Perrer N. Tosso, Lauren J. Scher, Wladek Minor, Milton L. Brown, Steven J. Metallo, Aykut Üren and Jeffrey A. Toretsky _

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Oncotarget. 2012; 3:172-182. https://doi.org/10.18632/oncotarget.454

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Abstract

Julie S. Barber-Rotenberg1, Saravana P. Selvanathan1, Yali Kong1, Hayriye V. Erkizan1, Tara M. Snyder2, S. Peter Hong3, Christina L. Kobs3, Natalie L. South3, Steven Summer3, Philip J. Monroe3, Maksymilian Chruszcz4, Veselin Dobrev5, Perrer N. Tosso1, Lauren J. Scher1, Wladek Minor4, Milton L. Brown1, Steven J. Metallo5, Aykut Üren1, and Jeffrey A. Toretsky1

1 Department of Oncology, Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC USA

2 AMRI, Pharmaceutical and Quality Services, Albany, NY USA

3 Battelle Memorial Institute, Health and Life Sciences, Columbus, OH USA

4 Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA USA

5 Department of Chemistry, Georgetown University, Washington, DC USA

Received: February 17, 2012; Accepted: February 26, 2012; Published: February 29, 2012;

Keywords: PRL-3 monoclonal antibody, PRL-3 mouse/human chimeric antibody, antibody therapy, intracellular oncoprotein

Correspondence:

Jeffrey A. Toretsky,

Abstract

Oncogenic fusion proteins, such as EWS-FLI1, are excellent therapeutic targets as they are only located within the tumor. However, there are currently no agents targeted toward transcription factors, which are often considered to be ‘undruggable.’  A considerable body of evidence is accruing that refutes this claim based upon the intrinsic disorder of transcription factors.  Our previous studies show that RNA Helicase A (RHA) enhances the oncogenesis of EWS-FLI1, a putative intrinsically disordered protein.  Interruption of this protein-protein complex by small molecule inhibitors validates this interaction as a unique therapeutic target.  Single enantiomer activity from a chiral compound has been recognized as strong evidence for specificity in a small molecule-protein interaction.  Our compound, YK-4-279, has a chiral center and can be separated into two enantiomers by chiral HPLC.  We show that there is a significant difference in activity between the two enantiomers.  (S)-YK-4-279 is able to disrupt binding between EWS-FLI1 and RHA in an immunoprecipitation assay and blocks the transcriptional activity of EWS-FLI1, while (R)-YK-4-279 cannot.  Enantiospecific effects are also established in cytotoxicity assays and caspase assays, where up to a log-fold difference is seen between (S)-YK-4-279 and the racemic YK-4-279.  Our findings indicate that only one enantiomer of our small molecule is able to specifically target a protein-protein interaction. This work is significant for its identification of a single enantiomer effect upon a protein interaction suggesting that small molecule targeting of intrinsically disordered proteins can be specific. Furthermore, proving YK-4-279 has only one functional enantiomer will be helpful in moving this compound towards clinical trials.


 


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