YK-4-279 Leads to Xenograft Regression by Three Days SK7ES1& 700" 500" 400" Control&(n=4)& 800" Racemic&(n=4)& 700" YK7S&(n=5)& Tumor&Vol.&(mm3)& Tumor&vol.&(mm3)& 600" A4573&& 900" YK7R&(n=4)& 300" 200" 600" Control&(n=4)& Racemic&(n=4)& YK@S&(n=5)& YK@R&(n=4)& 500" 400" 300" 200" 100" 100" 0" 0" 0" 1" 2" Days&a1er&treatment& 3" 0" 1" 2" Days&a1er&treatment& 16 3" Vehicle Control Racemic YK-4-279 R-YK-4-279 S-YK-4-279 Apoptosis TUNEL Assay Vehicle Control Racemic YK-4-279 R-YK-4-279 S-YK-4-279 Con'nuous*Infusion*(S)1YK141279*in* nude*rat*ES1*orthotopic*xenograB (avg*plasma*level*aBer*26*days*=*4.6*µM) 45 Cont #3 Cont #18 Cont #17 S-YK #6 S-YK #21 S-YK #10 S-YK #12 S-YK #20 S-YK #15 40 35 30 25 20 15 10 5 0 0 5 10 15 20 25 Days after treatment 30 35 40 #17 #21 Dans les champs de l'observation le hasard ne favorise que les esprits préparés. • In the fields of observation chance favors only the prepared mind. • Lecture, University of Lille (7 December 1854) Louis Pasteur EWS-FLI1 is an Intrinsically Disordered Protein (IDP) • IDP have wiggly shapes and no significant ‘fixed’ structure • High degree of charged amino acids • Wiggliness is THERMODYNAMICALLY favorable for small molecule binding • Most transcription factors have significant intrinsic disorder to facilitate PROTEIN INTERACTIONS • ...more on this over beer Fusion&Protein&TranscripEon&Factors& are&DRUGGABLE… Protein-small molecule interact through intrinsically disordered regions 2. Multiple function models demonstrate enantiospecificity of YK-4-279 3. Animal modeling corroborates PK data 4. Hopefully in the clinic in 12 months 1. Pediatric Oncology Laboratory Group Past Lab Members: Manju Thakar Naamah Zitomersky Amy Skervsky Yu-feng (Alfred) Sun Amy Levinson Kelsey McCarty Kevin Chen Lauren Jacobwitz Scher Danny Scher Alison O’Neill Ellen Gamble Ryan Commins Sarah Pickard Nilan Schnure Ogan Abaan Julie Barber-Rotenberg Elspeth Beauchamp Gulay Bulut Silke Schlottman Elizabeth Drebing Gabi Perazza Elizabeth Toretsky Nilay Shah, MD Emily Soni, MD + summer students/rotations Current Lab Members: Aykut Uren, MD Verda Erkizan. PhD Sung-Hyeok Hong, DVM Saravana Selvanathan, PhD Haydar Celik, PhD Manisha Taya Tsion Minas Yasmine Saygideger, MD Suthee Rapisuwon, MD Garrett Graham Jeff Schneider Kamal Sajan, MS Jenny Han Said Rahim + students/rotators Collaborators Biochemistry and Structural Biology • Thanemozhi Natarajan, Hongzhan Huang, Cathy H. Wu (Protein Information Resource) • Vladamir Uversky, USF • Sarah Bondos, Tx A & M • Vladek Minor, UVa • Maksimillan Chruz, U South Carolina • Tara Snyder, AMRI, Inc. Pharmacology • Anton Wellstein, GU • Peter Houghton, OSU Medicinal Chemistry • Milton Brown and Yali Kong, GU • Steve Metallo, GU • Angela Koehler, Broad Institute Ewings Stem Cell • David Loeb, JHH* *dual-PI R01 Misc. Supporters/Providers of Key Reagents • Melinda Merchant, NIH • Peter Hong, Battelle, Inc. • Jeff Parvin, Harvard • Tara Snyder, AMRI, Inc. • Marc Landanyi, MSKCC Current Support NIH, NCI (R01, R01, RC4) Burroughs-Wellcome Translational Scientist Award Past Support Children’s Cancer Foundation, Baltimore, MD Dani’s Foundation, Rutledge Foundation Go4theGoal CureSearch (AFLAC, Currey) Make Some Noise Liddy Shriver Sarcoma Initiative Amschwand Sarcoma Foundation Alex’s Lemonade Stand Foundation 28
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