Bardoxolone Derivatives as Novel Pseudo-Natural Necroptosis Inhibitors by Destabilizing HSP90 Client Proteins

Targeting necroptosis has been confirmed as an efficient treatment strategy for inflammatory diseases. 2-Cyano-3,12-dioxo-olean-1,9-diene-28-carboxylic acid (CDDO) was previously identified as a pseudonatural-product necroptosis inhibitor. However, CDDO was inactive in murine cells and less active in human cells. In this study, 27 derivatives of CDDO were synthesized by structural modification in A and D/E rings, among which <b>ZYH-23</b> had the best activity. It could effectively block necroptosis in both human and murine cells and soon alleviate SIRS-induced hypothermia and death by remarkably decreasing proinflammatory factors <i>in vivo</i>. For the mechanism, <b>ZYH-23</b> blocked necroptosis by targeting HSP90 to inhibit the phosphorylation of RIPK1, RIPK3, and MLKL. Notably, different from that of CDDO, <b>ZYH-23</b> could induce destabilizing HSP90 client proteins in a short-term treatment and in a proteasome- and lysosome-independent manner. In summary, the present study provided a series of novel pseudonatural inhibitory candidates for necroptosis-related diseases with a new mechanism.