Idiopathic pulmonary fibrosis (IPF) is a devastating lung disease. Patients face a 50% three-year mortality rate and no proven effective therapy exists. The primary goal of this project is to establish a medicinal chemistry core facility that supports translational research projects in our shared objective to develop new drug therapies for IPF. Project Pis hypothesize that IPF is a consequence of on-going epithelial stress and apoptosis, which leads to activation of extracellular latent TGF-beta by the alpha-v beta-6 integrin on alveolar epithelial cells, which in turn induces progressive fibrosis at least in part through induction of epithelial to mesenchymal transformation. A concept that unifies our drug development approach is that each of the mechanisms can be optimally targeted by delivering drug agents directly to the alveolar epithelial cells via the airways. Delivery by inhalation has the potential to minimize unwanted systemic effects, especially when the drug agent has low systemic availability. Early screening hits, tool compounds and lead compounds that target each of these mechanisms have been identified by Project Pis. The medicinal chemistry core will work collaboratively to optimize these compounds for superior potency, selectivity and pharmacokinetic profile (rapid clearance upon systemic absorption) to increase efficacy and therapeutic index in animal models of IPF with inhaled delivery. The objective for all of these activities is to identify clinical candidates for advancement to clinical trials in IPF under the planned second phase of this tPPG.

Public Health Relevance

We are working to develop new and efficacious treatments for idiopathic pulmonary fibrosis. Medicinal chemistry is a critical component of these efforts. Using these methods, lead compounds are improved upon through the iterative design and testing of new analogs. In conjunction with each project, improvements in properties like potency, selectivity and drug likeness will lead to the generation of drug candidates.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL108794-02
Application #
8527841
Study Section
Special Emphasis Panel (ZHL1-CSR-Q)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$349,081
Indirect Cost
$126,736
Name
University of California San Francisco
Department
Type
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Travis, Mark A; Sheppard, Dean (2014) TGF-* activation and function in immunity. Annu Rev Immunol 32:51-82
Wolters, Paul J; Collard, Harold R; Jones, Kirk D (2014) Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol 9:157-79
Ghosh, Rajarshi; Wang, Likun; Wang, Eric S et al. (2014) Allosteric inhibition of the IRE1? RNase preserves cell viability and function during endoplasmic reticulum stress. Cell 158:534-48
Xi, Ying; Tan, Kevin; Brumwell, Alexis N et al. (2014) Inhibition of epithelial-to-mesenchymal transition and pulmonary fibrosis by methacycline. Am J Respir Cell Mol Biol 50:51-60
Sheppard, Dean (2013) ROCKing pulmonary fibrosis. J Clin Invest 123:1005-6
Friedman, Scott L; Sheppard, Dean; Duffield, Jeremy S et al. (2013) Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 5:167sr1