Discovery And Bioevaluation Of Nur77-based Celastrol Derivatives With Improved Efficacy And Reduced Toxicity

The orphan nuclear receptor Nur77 is an immediate-early response gene that involved in numerous physiological and pathological processes,including inflammation,apoptosis and autophagy.Celastrol(also called "Thunder God Vine")traditionally used for treating inflammatory diseases has recently gained much attention worldwide due to its potent anti-cancer and anti-obesity activities.It has becoming one of the most promising natural active products with the same potential as artemisinin.Identification of the intracellular target mediating the therapeutic effects is therefore critical for developing new agents for clinical applications.Mitochondria plays a central role not only in energy production but also in cell death,immunity and inflammation.The organelle is very sensitive to damage from inflammatory insult,which is implicated in the development of numerous inflammatory diseases,such as cancer and metabolic diseases.Selective clearance of damaged mitochondria via autophagy(mitophagy)therefore represents a plausible mechanism for treating cancer and inflammatory diseases obesity.Recently,our laboratory discovered that celastrol exerts its anti-inflammatory and anti-obesity effect by directly targeting Nur77 to promote Nur77-dependent mitophagy.Because celastrol is extremely toxic,preventing it from clinical application,this discovery provides opportunities to identify improved celastrol derivatives for clinical development.This research project aims at identifying compounds that are more effective and less toxic by selectively targeting Nur77.We have designed and synthesized a series of celastrol derivatives.Their evaluation identified XS0503 as an improved compound that binds strongly to Nur77,inhibits inflammation and induces autophagy similar to celastrol.Importantly,Nur77-independent induction of apoptosis by celastrol is eliminated from XS0503.Our animal studies demonstrated that XS0503 could more effectively inhibit HFD-induced obesity than celastrol.Mechanistically,XS0503 could induce Nur77 interaction with TRAF2 and p62,leading to Nur77-dependent autophagy similar to celastrol.Taken together,our data reveal that the therapeutic effects and adverse toxicity of celastrol can be separated and identify a promising celastrol derivative with improved efficacy and reduced toxicity for treating obesity.