Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the US, yet currently there exist no treatments that can slow or prevent disease progression. A pathognomonic feature of COPD is the presence of sustained actions of bioactive mediators (e.g. matrix metalloproteinase (MMPs), and inflammasome-derived cytokines (IL-1 ?)) that produce chronic, unrelenting, airway inflammation and injury thereby contributing to the pathobiology of disease. We recently discovered a novel pathway for immunity through protein ubiquitination whereby a pro-inflammatory protein, called FBXO3 profoundly triggers cytokine secretion from cells (Nature Immunology 14:470-9, 2013). By targeting FBXO3, we developed a novel genus of small molecule inhibitors. Our pilot data indicate that (i) our lead drug, BC-1261, reduces circulating cytokines, alveolar inflammation, and prevents emphysema in a cigarette smoke exposure (CSE)-induced COPD murine model, (ii) that FBXO3 inhibitors inhibit CSE induced MMP and inflammasome activity, and that (iii) we have target validation where compared to wild-type FBXO3, COPD subjects with a naturally occurring protective, hypofunctional FBXO3 polymorphism (FBXO3V221I) have reduced cytokine levels, less severe emphysema, and disease progression. Hence, we will characterize BC-1261 as a new anti-inflammatory chemical entity for use in COPD preclinical models (UH2 Component), and demonstrate that BC-1261 exerts an optimal safety and drug product profile for in vivo use (UH3 Component). This application unveils a new molecular target (FBXO3) underlying COPD pathogenesis and a unique first-in-class compound targeting the ubiquitin-proteasome system for COPD. Execution of these studies will be the basis of a drug development program that will lead to a fundamental, paradigm-changing therapeutic advance for treatment of inflammation leading to an IND application setting the stage for a new translational initiative in COPD subjects.

Public Health Relevance

Emphysema and chronic bronchitis are major causes of death in the US and there are few treatments that prevent inflammation and slow disease progression. This inflammation is caused from the release of proteins, called cytokines and proteinases. We have discovered a new pathway of inflammation and discovered a unique drug that combats inflammation in emphysema. This discovery led us to propose a drug development program that eventually seeks approval by the FDA.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Program Officer
Postow, Lisa
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Weathington, Nathaniel M; Mallampalli, Rama K (2014) Emerging therapies targeting the ubiquitin proteasome system in cancer. J Clin Invest 124:6-12
Liu, Yuan; Mallampalli, Rama K (2014) Decoding the growth advantage of hypoxia-sensitive lung cancer. Am J Respir Crit Care Med 190:603-5
Chen, Yan; Li, Jin; Dunn, Sarah et al. (2014) Histone deacetylase 2 (HDAC2) protein-dependent deacetylation of mortality factor 4-like 1 (MORF4L1) protein enhances its homodimerization. J Biol Chem 289:7092-8
Zou, Chunbin; Mallampalli, Rama K (2014) Regulation of histone modifying enzymes by the ubiquitin-proteasome system. Biochim Biophys Acta 1843:694-702
Weathington, Nathaniel M; Snavely, Courtney A; Chen, Bill B et al. (2014) Glycogen synthase kinase-3? stabilizes the interleukin (IL)-22 receptor from proteasomal degradation in murine lung epithelia. J Biol Chem 289:17610-9