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RIP kinase inhibitors act on receptor-interacting protein kinases (RIPKs), mainly RIPK1, RIPK2 and RIPK3. RIPK1 and RIPK3 control necroptosis, a regulated form of necrosis triggered by tumor necrosis factor alpha (TNF-α) and other death receptor signals. Necrostatin-1 was described in 2005 as an inhibitor of nonapoptotic cell death, and RIPK1 was identified as its cellular target in 2008. A 2009 study showed that RIPK3 determines whether cells die by necrosis in response to TNF-α. GSK481 and PK68 are further RIPK1 inhibitors, and GSK-843 inhibits RIPK3. GSK583 inhibits RIPK2, which relays signals from the bacterial sensors nucleotide-binding oligomerization domain-containing proteins 1 and 2 (NOD1, NOD2).
