Novel Therapeutics for Pulmonary Hypertension
Abstract
Pulmonary hypertension (PH) is a fatal and progressive disease with a very poor prognosis. In patients with PH, the arteries that carry blood from the heart to the lungs become constricted. The resulting elevated pressure places tremendous strain on the heart and this can eventually lead to heart failure. The estimated median survival is only 2.8 years with a 5-year survival rate of 34%. Notably, PH is underdiagnosed in the U.S. Veteran population. The evaluation of medical reports from Service Members on active duty in theater and post-deployment health assessments have established a link between deployment-related exposures to sand, burn pits, and various chemicals with the onset of new respiratory symptoms. Given the high mortality associated with PH and the evidence suggesting an increased exposure-related risk for members of our military and Veteran populations to develop PH, more effective treatments with fewer side effects are urgently needed to improve the outcomes for those who have so bravely served our country. Autophagy is an evolutionarily conserved lysosomal-mediated cellular recycling process. Aberrant autophagy has been reported to contribute to the development and progression of PH by generating alternative sources of metabolic fuel to maintain cell survival under stress conditions and promote increased proliferation of pulmonary vascular endothelial cells (EC), pulmonary arterial (PA) smooth muscle cells (PASMC), and fibroblasts (FB). The critical role of autophagy in PH pathogenesis suggests that disrupting autophagic degradation may be a promising approach to treat the disease. We and others initially repurposed the Food and Drug Administration (FDA)-approved anti-malarial drug chloroquine (CQ) as a potential therapy for PH due to its off-target autophagy inhibitory effects. In vivo studies established proof of concept that disrupting autophagy at the lysosomal stage of the pathway with CQ had significant benefit in preventing the development of experimental PH and antagonizing the progression of active disease. However, clinical evidence indicates that CQ and its related analog hydroxychloroquine (HCQ) do not impair the pathway completely at tolerated doses and their continued use for this purpose is driven by the lack of better alternatives. This underscores both the challenge and opportunity to pursue novel chemical entities with drug-like properties to clinically target the autophagy pathway. We recently generated a series of novel orally available autophagy inhibitors that are significantly superior to CQ/HCQ. Our first hit, ROC-325, is 10 times more potent than HCQ, orally active, well tolerated, and demonstrated significant therapeutic benefit in its ability to prevent and treat PH in preliminary in vivo studies. We hypothesize that disrupting autophagy at the lysosomal stage is a novel therapeutic strategy for treatment of pulmonary arterial hypertension (PAH). Our major goal is to use state-of-the-art drug discovery tools and techniques to optimize the biological and pharmacological properties of the ROC-325 scaffold yielding a novel autophagy inhibitor that can be tested in a clinical trial for patients with PH and other disorders where autophagy contributes to disease pathogenesis. In Specific Aim 1, we will design and synthesize novel lysosomal autophagy inhibitors with optimized pharmacological properties. In Specific Aim 2, we will characterize the in vitro pharmacological properties and therapeutic effects of ROC-325 derivatives on PH. In Specific Aim 3, we will investigate the tolerability, efficacy, pharmacokinetics, and pharmacodynamics of optimized oral autophagy inhibitors in experimental PH mouse and rat models. We believe that our synergistic efforts and complementary expertise will produce first-in-class lead compounds for further development. Given the importance of autophagy to the pathogenesis of many diseases, it is expected that our new autophagy inhibitors will have broad the
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210319
Entities
People
- Jennifer Carew
Organizations
- United States Army
- University of Arizona