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)
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Special Emphasis Panel (ZHL1-CSR-A (M1))
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Postow, Lisa
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University of Pittsburgh
Internal Medicine/Medicine
Schools of Medicine
United States
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Suber, Tomeka; Wei, Jianxin; Jacko, Anastasia M et al. (2017) SCFFBXO17 E3 ligase modulates inflammation by regulating proteasomal degradation of glycogen synthase kinase-3? in lung epithelia. J Biol Chem 292:7452-7461
Han, SeungHye; Jerome, Jacob A; Gregory, Alyssa D et al. (2017) Cigarette smoke destabilizes NLRP3 protein by promoting its ubiquitination. Respir Res 18:2
Londino, James D; Gulick, Dexter L; Lear, Travis B et al. (2017) Post-translational modification of the interferon-gamma receptor alters its stability and signaling. Biochem J 474:3543-3557
Bednash, Joseph S; Weathington, Nathaniel; Londino, James et al. (2017) Targeting the deubiquitinase STAMBP inhibits NALP7 inflammasome activity. Nat Commun 8:15203
Zou, Chunbin; Synan, Matthew J; Li, Jin et al. (2016) LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1. J Cell Sci 129:51-64
Liu, Yuan; Mallampalli, Rama K (2016) Small molecule therapeutics targeting F-box proteins in cancer. Semin Cancer Biol 36:105-19
Krzysiak, Troy C; Chen, Bill B; Lear, Travis et al. (2016) Crystal structure and interaction studies of the human FBxo3 ApaG domain. FEBS J 283:2091-101
Chen, Wei; Xiong, Sheng; Li, Jin et al. (2015) The ubiquitin E3 ligase SCF-FBXO24 recognizes deacetylated nucleoside diphosphate kinase A to enhance its degradation. Mol Cell Biol 35:1001-13
Han, SeungHye; Mallampalli, Rama K (2015) The acute respiratory distress syndrome: from mechanism to translation. J Immunol 194:855-60
Londino, James D; Gulick, Dexter; Isenberg, Jeffrey S et al. (2015) Cleavage of Signal Regulatory Protein ? (SIRP?) Enhances Inflammatory Signaling. J Biol Chem 290:31113-25

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