Pharmacokinetic modeling optimizes inhibition of the ‘undruggable’ EWS-FLI1 transcription factor in Ewing Sarcoma
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Sung-Hyeok Hong1,*, Sarah. E. Youbi1,*, S. Peter Hong2, Bhaskar Kallakury3, Phillip Monroe2, Hayriye V Erkizan1, Julie S. Barber-Rotenberg1, Peter Houghton4, Aykut Üren1, Jeffrey A. Toretsky1
1 Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
2 Battelle Memorial Institute, Health and Life Sciences, Columbus, OH, USA
3 Department of Pathology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
4 Nationwide Children’s Research Institute, Center for Childhood Cancer, Columbus, USA
* These authors contributed equally
Jeffrey A. Toretsky, email:
Keywords: YK-4-279, EWS-FLI1, Ewing Sarcoma, rat xenograft, pharmacokinetic modeling
Received: October 11, 2013 Accepted: November 9, 2013 Published: November 11, 2013
Transcription factors have long been deemed ‘undruggable’ targets for therapeutics. Enhanced recognition of protein biochemistry as well as the need to have more targeted approaches to treat cancer has rendered transcription factors approachable for therapeutic development. Since transcription factors lack enzymatic domains, the specific targeting of these proteins has unique challenges. One challenge is the hydrophobic microenvironment that affects small molecules gaining access to block protein interactions. The most attractive transcription factors to target are those formed from tumor specific chromosomal translocations that are validated oncogenic driver proteins. EWS-FLI1 is a fusion protein that results from the pathognomonic translocation of Ewing sarcoma (ES). Our past work created the small molecule YK-4-279 that blocks EWS-FLI1 from interacting with RNA Helicase A (RHA). To fulfill long-standing promise in the field by creating a clinically useful drug, steps are required to allow for in vivo administration. These investigations identify the need for continuous presence of the small molecule protein-protein inhibitor for a period of days. We describe the pharmacokinetics of YK-4-279 and its individual enantiomers. In vivo studies confirm prior in vitro experiments showing (S)-YK-4-279 as the EWS-FLI1 specific enantiomer demonstrating both induction of apoptosis and reduction of EWS-FLI1 regulated caveolin-1 protein. We have created the first rat xenograft model of ES, treated with (S)-YK-4-279 dosing based upon PK modeling leading to a sustained complete response in 2 of 6 ES tumors. Combining laboratory studies, pharmacokinetic measurements, and modeling has allowed us to create a paradigm that can be optimized for in vivo systems using both in vitro data and pharmacokinetic simulations. Thus, (S)-YK-4-279 as a small molecule drug is ready for continued development towards a first-in-human, first-in-class, clinical trial.
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