Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in ewing sarcoma

Sung Hyeok Hong, Sarah E. Youbi, S. Peter Hong, Bhaskar Kallakury, Phillip Monroe, Hayriye V. Erkizan, Julie S. Barber-Rotenberg, Peter Houghton, Aykut üren, Jeffrey A. Toretsky

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

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 EWSFLI1 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.

Original languageEnglish (US)
Pages (from-to)338-350
Number of pages13
JournalOncotarget
Volume5
Issue number2
DOIs
StatePublished - 2014
Externally publishedYes

Keywords

  • EWS-FLI1
  • Ewing sarcoma
  • Pharmacokinetic modeling
  • Rat xenograft
  • YK-4-279

ASJC Scopus subject areas

  • Oncology

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