Receptor-interacting protein kinase 1 (RIPK1) is an important upstream kinase. Both scaffolding and kinase specific functions of RIPK1 can regulate inflammation. Recent work shows that active RIP1 kinase can drive this inflammation, which directly regulates programmed necrosis. Meanwhile, it also regulates the production of pro-inflammatory cytokines, inflammasome assembly, and some forms of pathogenic apoptosis. RIPK1 is a critical driver of inflammation, involving in various pathways downstream of the death receptors, such as TNFR1, FasL, TRAIL, and toll-like receptors. Hence, blocking this pathway has the potential to result in a broad therapeutic benefit for multiple inflammatory diseases.
GSK2982772 is an orally, potent and ATP competitive RIPK1 kinase inhibitor.
Moreover, it exerts IC50s of 16 nM and 20 nM for human and monkey RIPK1, respectively. In stimulated cellular systems, GSK2982772 reduces spontaneous production of cytokines, which is from ulcerative colitis explant tissue in overnight incubations. In addition, GSK2982772 produces a weak concentration dependent inhibition of hERG in human embryonic kidney (HEK-293) cells. It has an estimated IC50 of 195 μM. Meanwhile, it also shows a weak activation of the human Pregnane X receptor with an EC50 of 13 μM.
The mouse model evaluating protection from TNF induced lethal shock, GSK2982772 has been shown to be RIPK1 dependent. In this model, injection of TNF leads to a systemic inflammatory response, characterized by hypotension, hepatitis, hypothermia, and bowel necrosis over 6−7 h. In a similar model, injection of TNF combined with the caspase inhibitor zVAD leads to a similar but earlier onset systemic inflammatory response in about 3 h. The ability of the RIPK1 inhibitor to prevent body temperature loss measures the efficacy.
In summary, GSK2982772 has excellent activity in both RIPK1 cellular systems. Furthermore, it prevents TNF induced necrotic cell death, and an ulcerative colitis explant assay blocking spontaneous cytokine release. On the other hand, GSK2982772 has highly favorable physicochemical and pharmacokinetic properties. those suggest GSK2982772 is a first-in-class Clinical Candidate for the treatment of inflammatory diseases.
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.