Drug Design Of THPN Derivatives Based On The Structure Of Nur77

The nuclear receptor(NRs)superfamily is composed of evolutionarily related and structurally conserved transcription factors witih affinity for specific DNA sequences.In humans,48 NR genes have been identified.Nuclear receptors can interact w:ith other co-regulatory factors or proteins to perform transcriptional functions and act important roles of cell proliferation,poptosis,differentiation and other physiological activities.In addition,Nuclear receptors are associated with the appearance and development of multiple diseases.NRs are considered as the important drug targets for diseases.Nur77 belongs to the NR4A family,and the family has not found endogenous ligands up to date.Therefore,it is called orphan nuclear receptor Nur77 plays important roles in many physiological processes including cell survival,apoptosis,the dev?elopment of cancer,metabolism and inflammatory.The abnormal expression of Nur77 is associated with a variety of tumors.Drug designs targeting Nur77 are also of increasing interest.Previously,studies have shown that Nur77 acts in melanoma autophagic cell death via mitochondrial signaling pathway.A sequence of molecular events leading to cellular demise is launched by a specific chemical compound,1-(3,4,5-trihydroxyph-enyl)nonan-l-one(THPN).Thus,we have designed a series of derivatives of THPN based on the structure of Nur77 LBD and THPN complex.Two molecules interacting with Nur77 LBD were screened by crystallographic method.The molecules will be lead Nur77-targeting compounds.