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

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

AIR

Fibroblastic Focus

TREATMENT OPTIONS Fibroblastic focus Block formation Promote elimination

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

Let’s look under the hood

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

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

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

Translation Initiation Factor 4F A critical point of convergence

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

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

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

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

Where are we now?

The molecular target has a known structure

Compounds are designed and synthesized by University of Minnesota Medicinal Chemists

Does it work in a test tube?

Does it work in a fibroblast?

Does it work in a zebrafish embryo?

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

What’s next?

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

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