Vemurafenib inhibits necroptosis in normal and pathological conditions as a RIPK1 antagonist

Abstract

Necroptosis, a programmed cell death with necrotic-like morphology, has been recognized as an important driver in various inflammatory diseases. Inhibition of necroptosis has shown potential promise in the therapy of multiple human diseases. However, very few necroptosis inhibitors are available for clinical use as yet. Here, we identified an FDA-approved anti-cancer drug, Vemurafenib, as a potent inhibitor of necroptosis. Through direct binding, Vemurafenib blocked the kinase activity of receptor-interacting protein kinases 1 (RIPK1), impeded the downstream signaling and necrosome complex assembly, and inhibited necroptosis. Compared with Necrostain-1, Vemurafenib stabilized RIPK1 in an inactive DLG-out conformation by occupying a distinct allosteric hydrophobic pocket. Furthermore, pretreatment with Vemurafenib provided strong protection against necroptosis-associated diseases in vivo. Altogether, our results demonstrate that Vemurafenib is an effective RIPK1 antagonist and provide rationale and preclinical evidence for the potential application of approved drug in necroptosis-related diseases.

The regulated cell death at the maternal-fetal interface: beneficial or detrimental?

“…The inhibition of RCD has emerged as a potential strategy for treating a variety of human diseases. The anti-cancer drug vemurafenib can serve as an effective RIPK1 antagonist, effectively inhibiting necroptosis and the occurrence of related diseases [ 178 ]. The protective effect of mannose in inhibiting pyroptosis of normal gastrointestinal cells has been preliminarily confirmed in clinical trials involving gastrointestinal cancer patients undergoing chemotherapy [ 179 ].…”