RIPK1 (receptor-interacting protein kinase 1) is a serine/threonine protein kinase. It also is a key regulator of programmed cell necrosis (necroptosis). RIPK1 is closely related to the occurrence and development of various inflammatory and immune diseases. Firstly, RIPK1 will be activated when necroptosis is triggered by stimuli such as the tumor necrosis factor family of cytokine. Secondly, the activated RIPK1 associates with and phosphorylates its downstream protein RIPK3. Subsequently recruits and phosphorylates the pseudokinase mixed-lineage kinase domain like (MLKL). Finally, the phosphorylated MLKLs form oligomers and translocate to the cytomembrane to execute necroptosis. Owing to the central role of RIPK1 in necroptosis, RIPK1 inhibitor is crucial in early drug development. Generative deep learning (GDL) model can generate tailor-made virtual compound libraries for given biological targets. Further to discover the RIPK1 inhibitor–RI-962.
RI-962 is a potent, selective RIPK1 inhibitor and can protect cells from necroptosis.
Firstly, RI-962 can protect cells from necroptosis by inhibiting the kinase activity of RIPK1. RI-962 has potent inhibitory activity against RIPK1 with an IC50 value of 35.0 nM. RI-962 has protective effect for necroptotic death in HT29 cells, L929 cells, J774A.1 cells and U937 cells with EC50 values of 10.0 nM, 4.2 nM, 11.4 nM, and 17.8 nM, respectively. Besides, RI-962 has good pharmacokinetic (PK) in Sprague-Dawley (SD) rats. RI-962 exhibits a proper drug exposure, good clearance rate (CL) and metabolic stability. RI-962 shows well tolerated and no other side effects.Meanwhile, RI-962 can ameliorate TNFα-induced SIRS and reduces inflammation in acute DSS-induced colitis. In a word, RI-962 has good efficacy in vivo and vivtro inflammatory models.
To sum up, RI-962 is a potent and selective RIPK1 inhibitor. RI-962 can be used for the research of nervous system diseases and inflammatory diseases.