Preclinical Development of Small-Molecule Inhibitors Targeting Nox4 for Pulmonary Fibrosis
Abstract
Fibrosis or ?scarring? of vital internal organs is an increasing cause of debilitation and death worldwide. Human fibrotic disorders affect many organ systems including the heart, blood vessels, kidney, liver, and lungs. An estimated 45% of deaths in the U.S. are attributed to disorders that are characterized by varying degrees of fibrosis. This alarming statistic is often underappreciated since the ?cause of death? is often end-stage organ failure; however, organ failure is often attributed to progressive fibrosis. Further, the risk of organ fibrosis increases with age, accounting for a growing ?epidemic? of fibrotic disorders in aging populations in the U.S. Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive and fatal fibrotic lung disorder, which disproportionately affects the elderly/military populations. Although two drugs have recently gained Food and Drug Administration approval for IPF, no drug treatment has been shown to definitively improve quality of life for IPF patients and they have only been shown to delay death by 6 months. The current drugs only moderately slow the progression of lung decline. There are no available therapies which can ?reverse? fibrosis. Improved therapies for the treatment of IPF and other fibrotic diseases are needed in order to improve the patient experience and outcomes. Despite efforts by numerous groups to develop IPF treatments, progress has been aggravatingly slow. We offer two possible explanations for this discrepancy (both will be addressed in studies proposed within this application): (1) current preclinical animal models fail to reliably predict the success of drug candidates in human clinical trials and (2) although IPF is widely regarded as an age-related disease, drug treatments have not targeted age-associated pathologic mechanisms of IPF. Our group was the first to identify a novel role for the oxidant generating enzyme, NADPH oxidase-4 (Nox4), in mediating lung fibrosis; since then, Nox4 has also been implicated in a variety of fibrotic diseases, including the liver, skin, kidney, and heart. More recently, we demonstrated that Nox4 is aberrantly regulated in aging (persistently upregulated), leading to elevated oxidant generation (oxidative stress) and ultimately persistent (non-resolving) lung fibrosis. This previously unknown pro-fibrotic mechanism may help to explain why IPF develops more frequently in older individuals. Our proof-of-concept studies show that therapeutic targeting of Nox4 in aged mice with established fibrosis led to a reversal of persistent lung fibrosis. Although Nox4 is considered to be among the most promising targets for fibrotic disease, no selective Nox4 inhibitors are clinically available. We have screened over 30,000 compounds and through our medicinal chemistry and hit-expansion efforts, we have identified two novel classes of small-molecule inhibitors (series #1 and series #2) that are highly effective and selective in inhibiting Nox4. Our biophysical characterization studies demonstrate favorable qualities of our leads for subsequent clinical development. Two U.S. patent applications have been filed. The studies proposed within this application would enable the continued preclinical development of these novel Nox4 inhibitor drug candidates. Aim 1 is focused on medicinal chemistry efforts to complete hit expansion of lead series #1 and #2. The goal is to identify leads with increased efficacy and selectivity for Nox4, with favorable pharmacokinetic and pharmacodynamics properties, and to perform scale-up of these leads for subsequent formulation and animal studies. Aim 2 is focused on the formulation development of leads from each series for both oral and inhaled delivery routes; we believe that evaluating two delivery modalities will increase the likelihood of finding a safe and effective protocol for inhibiting Nox4 in the lungs. This aim will also evaluate the pharmacokinetics/pharmacodynamic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Aug 07, 2017
- Source ID
- W81XWH1710443
Entities
People
- Louise Hecker
Organizations
- United States Army
- University of Arizona