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Necrostatin-1 Analogues: Critical Issues On The Specificity, Activity And In Vivo Use In Experimental Disease Models., N Takahashi, L Duprez, S Grootjans, A Cauwels, W Nerinckx, J B Duhadaway, V Goossens, R Roelandt, F Van Hauwermeiren, C Libert, W Declercq, N Callewaert, G C Prendergast, A Degterev, J Yuan, P Vandenabeele

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Necrostatin-1 (Nec-1) is widely used in disease models to examine the contribution of receptor-interacting protein kinase (RIPK) 1 in cell death and inflammation. We studied three Nec-1 analogs: Nec-1, the active inhibitor of RIPK1, Nec-1 inactive (Nec-1i), its inactive variant, and Nec-1 stable (Nec-1s), its more stable variant. We report that Nec-1 is identical to methyl-thiohydantoin-tryptophan, an inhibitor of the potent immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). Both Nec-1 and Nec-1i inhibited human IDO, but Nec-1s did not, as predicted by molecular modeling. Therefore, Nec-1s is a more specific RIPK1 inhibitor lacking the IDO-targeting effect. Next, although Nec-1i was ∼100 × …