Small Molecule Inhibitors of the Inflammatory Cytokine Oncostatin M

点击翻译按钮获取中文摘要

PROJECT SUMMARY/ABSTRACT This project will synthesize and study small molecules inhibitors (SMIs) that bind to and inhibit signaling of the inflammatory cytokine, oncostatin M (OSM) as part of a long-term program to generate an FDA-approved drug for early protection against breast tumor metastasis and other OSM-associated diseases. In 2021, more than 281,000 new cases of invasive breast cancer are expected to be diagnosed in the United States. The five-year survival rate is 99% for patients diagnosed with localized disease but drops to 27% for those with distant metastases, underscoring a need for therapeutics that protect against the early stages of metastasis, when intervention could be most beneficial. Relevant to this proposal, OSM signaling promotes many metastatic- related events, including an epithelial to mesenchymal transition and tumor cell detachment, migration, and invasion. Importantly, OSM signaling is associated with a poor prognosis for breast cancer patients. Breast cancer patients with high levels of tumor tissue OSM correlated with a significant decrease in survival compared to those with low OSM levels. It was also determined that serum concentrations of OSM from both non-metastatic and metastatic breast cancer patients was significantly higher than levels in serum from healthy individuals (3.8-fold and 4.9-fold, respectively). For this proposal, preliminary experiments used a high throughput computational screen of ~1.65 million compounds for binding to OSM. Those compounds with the best predicted binding properties were tested for in vitro inhibition of OSM signaling. Two SMIs were identified as lead compounds for this proposal. The central hypothesis guiding the proposed experiments is that structural optimization based on lead SMIs, facilitated by knowledge of important binding interactions, will result in enhanced inhibition of OSM signaling. To test the hypothesis, two specific aims are proposed: 1) Design and synthesize a focused library of small molecule inhibitors of OSM based on the SMI-10 and SMI- 26 scaffolds and 2) Identify optimal lead SMIs that suppress OSM signaling in cells and display minimal cellular toxicity. In Aim 1, the NMR solution structure of an SMI/OSM complex will be solved and then combined with computational modeling to develop a structure-activity model that will be used to design and synthesize new SMIs. In Aim 2, SMIs will be prioritized based on high binding affinity, high in vitro inhibition of OSM-mediated signaling pathways in several breast cancer cell lines, and low cellular toxicity. The end goal of the project is to identify new compounds with nanomolar binding affinity to OSM and improved inhibitory activity. The proposed research will assist in fulfilling the critical need to develop novel treatments for metastatic breast cancer—often described as an “incurable” disease. Since OSM has been linked to other cancers and inflammatory-related diseases (e.g., sepsis, rheumatoid arthritis, and cystic fibrosis), this research lays the groundwork for a new class of anti-inflammatory drugs.