Study on identification of RIPK1 inhibitor for therapeutic potential RIPK1 stands out as a pivotal player controlling cell death and inflammation. Moreover, given that inhibition of RIPK1 kinase activity has been shown to be effective in animal models of human diseases such as autoimmune and neurodegenerative disorders, RIPK1 has been considered as an attractive therapeutic target. Specifically, owing to its unique allosteric pocket, RIPK1 kinase is ripe for small-molecule inhibitors. As a representative example, necrostatin-1 (Nec-1), a first small-molecule inhibitor of RIPK1 kinase, has been extensively used to exploring the function of RIPK1. Herein, we screened a collection of approved drug and ongoing clinical trial drugs with structural similarity to Nec-1 to assess their ability to regulate RIPK1-mediated cell death. Through this small-scale screen, we discovered that Phensuximide, already FDA approved drug as anti-epilepsy, can prevent with necroptosis by targeting RIPK1 kinase. Importantly, we identified that phensuximide effectively prevents RIPK1-dependent necroptosis in human and murine cell lines without affecting the NF-κB and MAPK pathway or apoptosis. Additionally, we show that phensuximide can protect against LPS-induced systemic inflammatory response syndrome (SIRS), which is an animal model of sepsis, and it involves RIPK1 kinase activity. Overall, our findings suggest that the already FDA- approved phensuximide may offer a new strategy for targeting RIPK1-mediated diseases. Keywords: RIPK1, Inflammation, Allosteric pocket, SIRS, Phensuximide
