RIPK1 inhibitor Cpd-71 attenuates renal dysfunction in cisplatin-treated mice via attenuating necroptosis, inflammation and oxidative stress

In this study, we evaluated the treatment effects of Cpd-71, a novel RIPK1 inhibitor, by comparing with Necrostatin-1 (Nec-1), a classic RIPK1 inhibitor, which has several drawbacks like the narrow structure activity relationship (SAR) profile, moderate potency and non-ideal pharmacokinetic properties, in vivo and in vitro . Our results showed that pretreatment of Cpd-71 attenuated cisplatin-induced renal injury, restored renal function, and suppressed renal inflammation, oxidative stress and cell necroptosis. In addition, Cpd-71 inhibited renal damage while reducing the upregulated serum creatinine and BUN levels in established AKI mice model. Consistently, we confirmed that Cpd-71 exhibited more effectively suppressive effect on cisplatin-induced renal tubular cell necroptosis than Nec-1, by physically binding to the allosteric type ligand binding site of RIPK1, thereby reduced RIPK1 kinase activity, RIPK1/RIPK3 complex formation, and phosphor-MLKL membrane translocation by molecular docking, western blot, co-immunoprecipitation and cellular thermal shift assay (CETSA). Taken together, we currently showed that targeting RIPK1 with Cpd-71 may serve as a promising clinical candidate for AKI treatment.

Source: Clinical Science - July 16, 2019 Category: Biomedical Science Authors: Wang, J.-n., Liu, M.-m., Wang, F., Wei, B., Yang, Q., Cai, Y.-t., Chen, X., Liu, X.-q., Jiang, L., Li, C., Hu, X.-w., Yu, J.-t., Ma, T.-t., Jin, J., Wu, Y.-g., Li, J., Meng, X.-M. Tags: PublishAheadOfPrint Source Type: research