Transcript IPF: How to approach the search for new therapies

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
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Growth Factor–Growth Factor Receptor1,2,3…i
PDGF, TGF, CTGF
Adaptor protein1,2,3…j
Signal transducer1,2,3…k
Ras, tyrosine kinase
Translation Initiation Factor
4F
A critical point of convergence
Drug Discovery
Identify Molecular Targets
• an “Achilles Heel”
Validate Molecular Targets
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When eIF4F is locked in the
on position, new biological
properties emerge
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Remove cells from the
fibroblastic focus
and study in a petri dish
•Proliferate
•Persist
•Produce scar tissue
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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
Gl u--103
Tr p-102
7-Me -GDP
Tr p-56
Hydrophobi c
Pocket
Compounds are designed
and synthesized by
University of Minnesota
Medicinal Chemists
Does it work in a test
tube?
Does it work in a fibroblast?
CAP-dept. translation (Renila Luc.)
Does it work
in a zebrafish embryo?
60 00 000
50 00 000
40 00 000
30 00 000
20 00 000
10 00 000
0
12 .09 .0 4
RNA 2 00 pg
51 67 960
PG18 0 25 pM
36 21 763
PG18 0 2.5 pM
34 35 383
CON (n on -inj.)
43 12 2
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
• US taxpayers who
support the NIH
Vitaly Polunovsky
• Generous alumni and
Mark Peterson
benefactors
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…