Scaffold hopping derived novel benzoxazepinone RIPK1 inhibitors as anti-necroptosis agents

Receptor-interacting protein kinase 1 (RIPK1)-mediated necroptosis is believed to have a significant role in contributing to inflammatory diseases. Inhibiting RIPK1 has shown promise in effectively alleviating the inflammation process. In our current study, we employed scaffold hopping to develop a series of novel benzoxazepinone derivatives. Among these derivatives, compound o1 displayed the most potent antinecroptosis activity (EC50 = 16.17 & PLUSMN; 1.878 nM) in cellular assays and exhibited the strongest binding affinity to the target site. Molecular docking analyses further elucidated the mechanism of action of o1, revealing its ability to fully occupy the protein pocket and form hydrogen bonds with the amino acid residue Asp156. Our findings highlight that o1 specifically inhibits necroptosis, rather than apoptosis, by impeding the RIPK1/Receptor-interacting protein kinase 3 (RIPK3)/mixed-lineage kinase domain-like (MLKL) pathway's phosphorylation, triggered by TNF & alpha;, Smac mimetic, and z-VAD (TSZ). Additionally, o1 demonstrated dose-dependent improvements in the survival rate of mice with Systemic Inflammatory Response Syndrome (SIRS), surpassing the protective effect observed with GSKMODIFIER LETTER PRIME772.

Automated summary

In this study, novel benzoxazepinone derivatives were synthesized and compound o1 exhibited the most potent antinecroptosis activity and the strongest binding affinity to the target site. Molecular docking analyses revealed that o1 fully occupied the protein pocket and formed hydrogen bonds with the amino acid residue Asp156. Moreover, o1 specifically inhibited necroptosis by blocking the phosphorylation of RIPK1/RIPK3/MLKL pathway and showed dose-dependent improvements in the survival rate of mice with Systemic Inflammatory Response Syndrome (SIRS) compared to GSKMODIFIER LETTER PRIME772.