A RIPK1 inhibitor
GSK2982772 is a potent and ATP competitive RIP1 inhibitor with an IC50 of 16 nM.
GSK2982772 shows more than 1,000-fold selectivity for ERK5 over a panel of over 339 kinases at 10 uM. In stimulated cellular systems,GSK2982772 is also able to reduce spontaneous production of cytokines (IL-1β and IL-6) in a concentration-dependent fashion from ulcerative colitis explant tissue in overnight incubations. GSK2982772 produces a weak concentration dependent inhibition of hERG in human embryonic kidney (HEK-293) cells, with an estimated IC50 of 195 uM, and also shows a weak activation of the human Pregnane X receptor (hPXR) with an EC50 of 13 uM[1].
GSK2982772 is dosed orally 15 min prior to TNF and shows 68, 80, and 87% protection from temperature loss over 6 h, at doses of 3, 10, and 50 mg/kg, respectively. In the corresponding TNF/zVAD model, GSK2982772 shows 13, 63, and 93% protection from temperature loss over 3 h. GSK2982772 displays a good free fraction in blood in rats (4.2%), dogs (11%), cynomolgus monkeys (11%), and humans (7.4%). The inhibitor has a good pharmacokinetic profile across both rats and monkeys. GSK2982772 distributes into a range of tissues including the colon, liver, kidney, and heart at concentrations comparable to those of blood. However, GSK2982772 has low brain penetration in rat (4%) despite possessing good cell permeability (21×10-6 cm/s)[1].
参考文献:
[1]. Harris PA, et al. Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases. J Med Chem. 2017 Feb 23;60(4):1247-1261.
Animal experiment: | Mice: A total of 7 mice per dose group are orally predosed with saline or GSK2982772 at doses of 3, 10, and 50 mg/kg 15 min before i.v. administration of mouse TNF (30 μg/ mouse). Temperature loss in the mice is measured by a rectal probe. The study is terminated after 6 h when the control group lost 7 °C[1]. |
参考文献: [1]. Harris PA, et al. Discovery of a First-in-Class Receptor Interacting Protein 1 (RIP1) Kinase Specific Clinical Candidate (GSK2982772) for the Treatment of Inflammatory Diseases. J Med Chem. 2017 Feb 23;60(4):1247-1261. | |
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