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 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.
Highlights
Ewing Sarcoma (ES) is a rare cancer of bone or soft tissue that affects 3 people per million each year, largely adolescents between the ages of 10 and 25 [1]
The interaction between EWS-FLI1 and RNA Helicase A (RHA) is critical for driving ES transformation [6], and the small molecule YK-4-279 disrupts the interaction between EWS-FLI1 and RHA leading to apoptotic cell death [7]
Cells were treated for the indicated exposure time replated without YK-4-279 to assay for colony formation (Figure 1A)
Summary
Ewing Sarcoma (ES) is a rare cancer of bone or soft tissue that affects 3 people per million each year, largely adolescents between the ages of 10 and 25 [1]. Those diagnosed with local disease experience a 5-year survival rate of 73%, while those with metastatic disease have a survival of 20-30% after 2-3 years [2,3,4]. IDP-drug interactions are generally highly specific, with low affinity lending to reversible binding between the protein and drug [13,14,15]. EWS-FLI1 is recognized as an ideal anticancer target, yet in part due to these perceived biochemical challenges, no small molecule has entered the clinic that directly targets this key oncoprotein
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