Research Project
9620398
Idiopathic pulmonary fibrosis (IPF) is the most common and severe fibrotic lung disease in older adults and lacks any highly effective therapy. Emerging evidence indicates that loss of proteostasis in the alveolar epithelium contributes to the pathogenesis of IPF and several other fibrotic pulmonary conditions. In recent work, we uncovered that treating mice with a dual Liver-X Receptor-alpha/beta (LXR-?/?) agonist T0901317 (1) effectively reduced proteostasis in the lung epithelium, as visualized by changes in multiple relevant ER stress markers, and also markedly reduced the severity of fibrotic remodeling in the lung after exposure to silica. The rationale for selecting an LXR agonist for treating pulmonary fibrosis was based on the understanding that lipid synthesis is needed to resolve ER stress (membrane expansion) in many other models and our own published and pilot studies showing that levels of lipid synthesis enzymes are markedly reduced in mouse and human lung in pulmonary fibrosis. In pilot studies, the pharmacological approach utilized for inducing lipid synthesis was to activate the LXR, which is known to drive expression of many lipid synthesis genes. Importantly, LXR activation is a validated therapeutic target in drug discovery. However, LXR activation is known to cause upregulation of liver triglycerides, which could lead to long-term side effects such as fatty liver or atherosclerosis. Therefore, in this application we will adopt an innovative soft drug approach to target- mediated activation of LXR. This approach utilizes medicinal chemistry to synthesize agonists that work robustly in the lung but are rapidly converted into inactive compounds once entering the circulation. To achieve this goal, our proposal is divided into four Specific Aims. In Aim 1 we will design and synthesize soft LXR-?/? agonists suitable for pulmonary administration but which undergo rapid metabolism upon absorption into the circulation. In Aim 2 we will further evaluate these compounds by assessing activity, binding, and general cytotoxicity in vitro. Each new test compound will be designed to minimize the chance that metabolic fragments would have LXR activity on their own. Agonist potency of an EC50 <0.2 µM at either or both LXR- ?/?, a potency achieved by other active LXR agonists, and a therapeutic index (TI) of >100X would be required to advance to Aim 3, which will confirm rapid metabolic clearance (t1/2 < 10 mins) upon absorption using mouse and human plasma, liver microsomes and hepatocytes. In the fourth Aim, 2-3 compounds will be evaluated for their ability to induce lipid synthesis, reduce ER stress and limit pulmonary fibrosis in mice. For these studies, we will employ the bleomycin injury model. LXR activation with lung-specific delivery followed by rapid metabolic clearance after absorption is a particularly unique application of the soft-drug approach in therapy. At the end of the proof of concept Phase I stage, we will have validated the soft drug approach for treating pulmonary fibrosis and be ready to test the efficacy of our compounds in additional and more clinically relevant animal models during expanded drug discovery and lead optimization in Phase II.
