RIPA-56

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 µM, as well as over a panel of additional kinases at 2 µM. 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

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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 syndrome. J. 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 elevation. Proc. Natl. Acad. Sci. USA 116(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 disease. J. Hepatol. 72(4), 627-635 (2020).