Discovery And Bioevaluation Of Nur77-selective Celastrol Anologs

Nuclear receptors are transcription factors involved in diverse physiological and pathological processes.Orphan nuclear receptor Nur77 plays an important role in many physiological processes,such as apoptosis,proliferation,autophagy and metabolism.Nur77 has also emerged as a critical regulator of the onset and progression of cancer,metabolic and inflammatory diseases.Autophagy is a crucial regulatory mechanism for cell survival and homeostasis.Mitophagy is a selective form of autophagy,and responsible for the removal of damaged mitochondria.Autophagy functions in immune and inflammatory responses,and selective clearance of dysfunctional or damaged mitochondria during inflammation represents an important mechanism to maintain a successful inflammatory response.Celastrol is a potent anti-inflammatory pentacyclic triterpene isolated from the root of Tripterygium wilfordii,which has been used as a traditional Chinese medicine for treating arthritis.As a potent anti-inflammatory drug,the therapeutic usefulness of celastrol has been explored in various diseases,including rheumatoid arthritis,Alzheimer’s disease,asthma,and cancer.In addition,it was recently shown to possess potent anti-obesity activity.But,intracellular proteins mediating the anti-inflammatory effects of celastrol remain unknown.Hence,the identification of the protein factors is crucial in developing celastrol-based drugs.Recently,our lab discovers Nur77 as a direct target of celastrol,and reports a new Nur77-dependent mitophagic mechanism,in which celastrol-induced Nur77 mitochondrial targeting and interaction with TRAF2 and p62 lead to clearance of damaged mitochondria caused by prolonged inflammatory stimulation,therefore alleviating inflammation.Although celastrol is a very promising drug candidate,it has serious side effects that exclude it from clinical application.Our identification of Nur77 as a direct celastrol target offers an opportunity to develop celastrol analogs with reduced adverse effects.In this study,we synthesize a series of celastrol analogs,and our bioevaluation reveals that XS0284,with better solubility than celastrol,could selectively binds Nur77 and induces Nur77-dependent clearance of damaged mitochondria through motophagy.Our results therefore identify XS0284 as a new celastrol analog that selectively targets Nur77 for inhibiting inflammation with desirable therapeutic profiles,representing a promising lead warranting further evaluation and development.