Soft LXR Agonists for the Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosisIPFis the most common and severe fibrotic lung disease in older adults and lacks any highly effective therapyEmerging evidence indicates that loss of proteostasis in the alveolar epithelium contributes to the pathogenesis of IPF and several other fibrotic pulmonary conditionsIn recent workwe uncovered that treating mice with a dual Liver X Receptor alpha betaLXRagonist Teffectively reduced proteostasis in the lung epitheliumas visualized by changes in multiple relevant ER stress markersand also markedly reduced the severity of fibrotic remodeling in the lung after exposure to silicaThe rationale for selecting an LXR agonist for treating pulmonary fibrosis was based on the understanding that lipid synthesis is needed to resolve ER stressmembrane expansionin 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 fibrosisIn pilot studiesthe pharmacological approach utilized for inducing lipid synthesis was to activate the LXRwhich is known to drive expression of many lipid synthesis genesImportantlyLXR activation is a validated therapeutic target in drug discoveryHoweverLXR activation is known to cause upregulation of liver triglycerideswhich could lead to long term side effects such as fatty liver or atherosclerosisThereforein this application we will adopt an innovative andquot soft drugandquotapproach to targetmediated activation of LXRThis approach utilizes medicinal chemistry to synthesize agonists that work robustly in the lung but are rapidly converted into inactive compounds once entering the circulationTo achieve this goalour proposal is divided into four Specific AimsIn Aimwe will design and synthesize soft LXRagonists suitable for pulmonary administration but which undergo rapid metabolism upon absorption into the circulationIn Aimwe will further evaluate these compounds by assessing activitybindingand general cytotoxicity in vitroEach new test compound will be designed to minimize the chance that metabolic fragments would have LXR activity on their ownAgonist potency of an ECandltM at either or both LXRa potency achieved by other active LXR agonistsand a therapeutic indexTIof andgtX would be required to advance to Aimwhich will confirm rapid metabolic clearancetandltminsupon absorption using mouse and human plasmaliver microsomes and hepatocytesIn the fourth Aimcompounds will be evaluated for their ability to induce lipid synthesisreduce ER stress and limit pulmonary fibrosis in miceFor these studieswe will employ the bleomycin injury modelLXR activation with lung specific delivery followed by rapid metabolic clearance after absorption is a particularly unique application of the soft drug approach in therapyAt the end of the proof of concept Phase I stagewe 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 Idiopathic pulmonary fibrosisPDFis a debilitating orphan condition affects andgtpatients in the USand for which there are few therapeutic treatment optionsHere we propose an entirely new approach for treating IPF involving andquot soft Liver X ReceptorLXRagonistsandquotthat act upon delivery to the lungs but are then rapidly cleared by metabolism to avoid general systemic effects elsewhere