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Jeffrey Toretsky Department of Oncology and Pediatrics Lombardi Comprehensive Cancer Center

Therapeutic Targeting of EWS-FLI1: Small Molecule Protein-Protein Interaction Inhibitors Prevent Xenograft Growth. Jeffrey Toretsky Department of Oncology and Pediatrics Lombardi Comprehensive Cancer Center Georgetown University Washington, DC. E wing’s S arcoma F amily of T umors.

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Jeffrey Toretsky Department of Oncology and Pediatrics Lombardi Comprehensive Cancer Center

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  1. Therapeutic Targeting of EWS-FLI1: Small Molecule Protein-Protein Interaction Inhibitors Prevent Xenograft Growth Jeffrey Toretsky Department of Oncology and Pediatrics Lombardi Comprehensive Cancer Center Georgetown University Washington, DC

  2. Ewing’sSarcoma FamilyofTumors • 1983: t(11;22) by standard g-banded karyotype • 1992: Breakpoint of t(11;22) cloned; EWS constitutively expressed • Derived chromosome 22 expressed as EWS-FLI1 11 der11 22 der22 • Elimination of EWS-FLI1 from ESFT cells is lethal

  3. 11 22 Transformation Transcription Factor Biology Translation Nucleus Cell Membrane Fusion Gene or Message Fusion Protein

  4. RHA EWS-FLI1 EWS-FLI1 Progression from Oncogene to Protein Partner to Poison RNA Helicase A (RHA) Peptide blocks RHA from binding to EWS-FLI E9R = PPPLDAVIEA Uren, Biochemistry 2004 Toretsky, Cancer Res 2006

  5. Mutant RHA fails to enhance EWS-FLI1 dependent transformation Anchorage independent growth 600 400 Colonynumbers 200 0 EWS-FLI1 RHA RHA-D827A FLAG-RHA 150 75 EWS-FLI1

  6. RHA peptide inhibits ESFT growth NES E9R EGFP E9R-P EWS/FLI1 pGE9R E9R EGFP pGCE9R

  7. NSC635437 in Druggable Space Peptide Model: Region of Overlap with Lead Compound P823 P824 P825 L826 A828 D827 GFP-E9R 10 aa peptide V829 E831 I830 A832

  8. Screening Library for Potential Binding

  9. Small molecule synthesis and optimization • NCI Compound NSC635437 synthesized at GU • Identified Lead with Homology to Peptide E9R • Analogs were synthesized • YK-4-279 selected based upon binding, EWS-FLI1:RHA disruption, and cytotoxicity profile

  10. YK-4-279 blocks RHA binding to EWS-FLI1

  11. YK-4-279 displaces E9R from EWS-FLI1

  12. YK-4-279 reduces EWS-FLI1 transcription activity

  13. YK-4-279 toxicity against EF compared to non-EF cell lines

  14. YK-4-279 Inhibits ESFT Xenografts

  15. Summary • Validated EWS-FLI1:RHA as molecular target • SPR screen identified small molecule lead • YK-4-279 demonstrates relative specificity with • 1 microM IC50 againstESFT • Xenograft studies • Further chemical optimization underway • To be followed by ADME/tox • Hopeful to advance to clinical trials

  16. Collaborators •Milton Brown and Yali Kong, GU, LCCC •David Loeb, JHH •Melinda Merchant, NIH •Angela Koehler, Broad Institute •Anton Wellstein, GU, LCCC •Steve Lessnick and Leah Owen, Utah •Olga Tscherkasskaya, GU •Jeff Parvin, Harvard •Michael Grusby, Harvard •Sean Lee, NIH •Marc Landanyi, MSKCC •Tim Cripe, Cincinnati Children’s

  17. Support • Children’s Cancer Foundation, Baltimore, MD • Dani’s Foundation • Go4theGoal • Liddy Shriver Sarcoma Initiative • Amschwand Sarcoma Foundation • CureSearch, NCCF • NIH, NCI • Burroughs-Wellcome • Translational Scientist Award

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