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 ZYH-23 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 in vivo. For the mechanism, ZYH-23 blocked necroptosis by targeting HSP90 to inhibit the phosphorylation of RIPK1, RIPK3, and MLKL. Notably, different from that of CDDO, ZYH-23 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.