RIPA-56 is an inhibitor of receptor interacting serine/threonine kinase 1 (RIPK1; IC50 = 13 nM).1 It is selective for RIPK1 over RIPK3 at 10 ?M, as well as over a panel of additional kinases at 2 ?M. RIPA-56 inhibits Z-VAD-FMK-induced necrosis in HT-29 cells (EC50 = 28 nM). In vivo, RIPA-56 (6 mg/kg) reduces TNF-α-induced lethality and protects against TNF-α-induced organ damage in a mouse model of systemic inflammatory response syndrome (SIRS). It reduces spinal cord demyelination and breakdown of the blood-brain barrier (BBB) in a mouse model of experimental autoimmune encephalomyelitis (EAE).2 RIPA-56 (300 mg/kg) reduces hepatic inflammatory cell infiltration and fibrosis, as well as body weight gain and total fat mass, in a mouse model of high-fat diet-induced non-alcoholic steatohepatitis (NASH).3
1.Ren, Y., Su, Y., Sun, L., et al.Discovery of a highly potent, selective, and metabolically stable inhibitor of receptor-interacting protein 1 (RIP1) for the treatment of systemic inflammatory response syndromeJ. Med. Chem.60(3)972-986(2017) 2.Zhang, S., Su, Y., Ying, Z., et al.RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevationProc. Natl. Acad. Sci. USA116(12)5675-5680(2019) 3.Majdi, A., Aoudjehane, L., Ratziu, V., et al.Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver diseaseJ. Hepatol.72(4)627-635(2020)