JNKinhibitors for the treatment of inflammation and endometriosis [epithelial cells]

Endometriosis is a prevalent gynecological disease that impact ~10% of women of reproductive age. In addition to causing chronic pain, and inflammation, women with endometriosis experience high rates of infertility, migraine, inflammatory bowel disease and autoimmune conditions. In this study, the efficacy of newly developed inhibitors of the c-Jun N-terminal kinases (JNK) were tested as therapeutics for endometriosis. Using state-of-the-art DNA encoded library screens, JNK inhibitors CDD-2728 and CDD-3013, with high specificity and efficacy were identified and tested in in vitro models of endometriosis. The ability of the inhibitors to decrease inflammation-related gene expression were evaluated in immortalized cell models of endometriosis, 12Z cells, and in primary derived endometriotic stromal cells from patients with the disease. Transcriptomic profiling was performed, as well as endpoints related to cell viability, cytotoxicity, and apoptosis. These studies identified that CDD-2728 and CDD-3013 were potent suppressors of IL1beta-induced inflammation, decreasing the expression of classical markers of inflammation, such as IL6, IL8, IL18, and PTGS2.