A specific and potent small-molecule inhibitor of necroptosis, necrostatin-1 (Nec-1) has been identified by screening for chemical inhibitors of necrotic cell death in U937 cellsi nduced by TNF-a in the presence of caspase inhibitors. Nowadays, several structurally and functionally distinct necrostatins and corresponding modifications have been reported.

 

The initial study showed that Nec-1 inhibits RIP kinase-induced necroptosis. This finding was confirmed later, when RIP1 kinase was identified as a specific cellular target of Nec-1, Nec-3 and Nec-5, but through distinct mechanisms. Nec-1 was shown to inhibit RIP1 kinase in a T-loop-dependent manner, binding preferentially to and stabilizing the inactive conformation of RIP1 kinase, thereby shifting the equilibrium toward the inactive state. In contrast to the mechanism of Nec-1 it was shown that Nec-5 inhibits RIP1 kinase indirectly. Those findings underline the critical role of active RIP1 kinase for necroptosis.

Necroptosis Inhibitors at AG Scientific, Inc.

Necrostatin-1 (CAS 4311-88-0)

Inhibits necroptosis, a non-apoptotic cell death pathway. Does not inhibit FAS-induced apoptosis and has no effect on apoptotic morphology. Inhibits RIP1 kinase, the key upstream kinase involved in the activation of necroptosis (EC = 180 nM).

Necrostatin-5 (CAS 337349-54-9)

Necroptosis inhibitor. Has displayed inhibition of RIP kinase indirectly. A potent inhibitor of immunopreciptated, but not recombinant RIP1.

 

Inhibits non-apoptotic cell deathpathway by inhibition of the death domain receptor-associated adaptor kinase RIP1. Three distinct mechanisms appear to be involved in necroptosis, the alternative active cell death pathway: T-loop dependent inhibition by necrostatin-1; partially T-loop independent inhibition by necrostatin-3 and indirect inhibition of RIP1 by necrostatin-5A.

Necrostatin-7 (CAS 351062-08-3)

A necroptosis inhibitor. The biological activity of necrostatin-7 (Nec 7) is different from that of necrostatin 1 to necrostatin 5 as Nec 7 does not inhibit RIP1 kinase. Nec-7 may target an additional regulatory molecule in the pathway.

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