2. IPF: How to approach the search for new therapies Peter Bitterman MD Research Director, Lillehei Heart Institute Professor of Medicine University of Minnesota

3. What is wrong in IPF? What appears to be normal scar tissue is deposited in the gas exchange surface of the lung University of Minnesota

4. AIR

5. Fibroblastic Focus

6. TREATMENT OPTIONS Fibroblastic focus Block formation Promote elimination

7. Drug Discovery Identify Molecular Targets an “Achilles Heel” Validate Molecular Targets Synthesize and Test Compounds University of Minnesota

8. Let’s look under the hood

9. Pathological Persistence of Cells In normal healing, fibroblasts choose to die when the wound space is filled – remember what happens to the cells in a tadpole’s tail. In fibrosis, the fibroblasts hang around. University of Minnesota

10. Is there another disease where cells appear when and where we don’t want them, and hang around when they shouldn’t? Cancer University of Minnesota

11. Growth Factor–Growth Factor Receptor 1,2,3…i Adaptor protein 1,2,3…j Signal transducer 1,2,3…k PDGF, TGF, CTGF Ras, tyrosine kinase

12. Translation Initiation Factor 4F A critical point of convergence

14. Drug Discovery Identify Molecular Targets an “Achilles Heel” Validate Molecular Targets University of Minnesota

15. When eIF4F is locked in the on position, new biological properties emerge University of Minnesota

16. Proliferate Persist Produce scar tissue Remove cells from the fibroblastic focus and study in a petri dish University of Minnesota

17. Drug Discovery Identify Molecular Targets an “Achilles Heel” Validate Molecular Targets Synthesize and Test Compounds University of Minnesota

18. Where are we now?

19. The molecular target has a known structure

20. Compounds are designed and synthesized by University of Minnesota Medicinal Chemists

21. Does it work in a test tube?

22. Does it work in a fibroblast?

23. Does it work in a zebrafish embryo?

24. Does it disturb development of the zebrafish embryo? Lead compound cycloheximide

25. What’s next?

26. Modify to increase potency Preclinical Testing Patent Transfer to private sector partner R and D Phase 1, 2 and 3 trials Rx University of Minnesota

27. Vitaly Polunovsky Mark Peterson Svetlana Avdulov J. Carlos Manivel Jose Jesserun Shunan Li Van Michalek David Burrichter David Perlman Douglas Yee Robert Kratzke Nahum Sonenberg (McGill, Montreal) O. Larsson (Karolinska, Stockholm) Thanks to… US taxpayers who support the NIH Generous alumni and benefactors