A RIPK1 inhibitor
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)
Cell experiment: | Cell necrosis assay is performed in 96-well cell culture plate. 3,000 cells are plated in each well and cultured at 37°C overnight. HT-29 cells are treated with 20 ng/mL TNFα/100 nM Smac Mimetics/20 μM z-VAD-FMK and RIPA-56 for 24 h. L929 cells are treated with 20 ng/mL TNFα/20 μM z-VAD-FMK and RIPA-56 for 6 h. The cell survival ratio is determined using the Cell Titer-Glo Luminescent Cell Viability Assay kit[1]. |
Animal experiment: | Mice: Following intraveneous (IV), intraperitoneal (IP), or oral administration (PO) of RIPA-56 to C57BL/6 mice (n=3), blood is sampled through eye puncture at various time points. Compound concentrations in the plasma samples are analyzed by LCMS/MS. Pharmacokinetic parameters are determined from individual animal data using noncompartmental analysis in phoenix 64[1]. |
参考文献: [1]. Ren Y, et al. Discovery of a Highly Potent, Selective, and Metabolically Stable Inhibitor of Receptor-InteractingProtein 1 (RIP1) for the Treatment of Systemic Inflammatory Response Syndrome. J Med Chem. 2017 Feb 9;60(3):972-986. | |
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