Part of the focus of my lab is centered on the analysis of the roles of RIPK1/3 kinases in necroptosis and inflammation, and development of small molecule inhibitors of this kinase family. I have successful ongoing collaborations with the Balachandran and Cuny labs that instigated work leading to the current proposal. With Balachandran, I outlined the mechanism of necroptosis triggered by the interferon family of antiviral cytokines (Thapa et al., PNAS 2013) and identified new roles for RIPK1/3 in production of these cytokines during TLR-initiated inflammatory responses (Saleh et al., J. Immunol 2017). We also outlined a new signaling pathway of downstream of RIPK1 and RIPK3 that drives pro-inflammatory gene expression via ERK1/2 and NF-�B pathways (Najjar et al., Immunity 2016), and collaborates with necroptosis to promote pathogenic inflammation. Finally, all three of us (Degterev, Cuny, Balachandran) collaborated on identifying Ponatinib and other pan-kinase inhibitors as potent blockers of RIPK1/3-driven necroptosis (Najjar et al, Cell Reports 2015). This study highlights our ability to work as a team and supplies evidence of our capacity to successfully identify new inhibitors of RIPK3. We are excited to come together for studies outlined in the current proposal: our new series of UH15-based compounds offers the distinct possibility of first-in-class RIPK3 inhibitors for a range of inflammatory diseases, most of which have limited or no current treatment options.