Design And Development Of PDNPA Derivatives Targeting Nur77

Nuclear receptors(NR)participate in various cellular and disease processes,which play a key role in life process.nuclear receptors are important drug targets.Nur77 is classified as an orphan nuclear receptor.Nur77 participates in various cellular processes including cell proliferation and differentiation apoptosis,autophagy,and so on.In addition Nur77 can either promot cancer cell growth,inhibit cancer growth,or faciliate cell apoptosis in the development of many tumors.Therefore,the study of Nur77 related structure and function has important theoretical significance and practical value.PDNPA is an anti-inflammatory small molecule inhibitor targeting Nur77,and the mechanism of its anti-inflammatory effect provides a new idea for the research and development of anti-inflammatory drugs.Therefore,the design of derivatives based on the binding mode of PDNPA and Nur77 LBD is an attractive research direction.According to the complex structure of PDNPA and Nur77 and the previous work in the laboratory,using the principles and techniques of organic chemistry,to this end,6 macrocyclic derivatives of PDNPA were synthesized and their structures were verified by 1H-NMR and mass spectrometry.The Ligand Binding Domain(LBD)of Nur77 was expressed and purified by means of molecular biology and biochemistry.Using Thermal Shift Assay technology to simply test the binding of 6 small molecules with Nur77 in vitro.The complex structures of two of these compounds,C2 and C3,with Nur77 LBD were analyzed by X-ray crystallography and briefly analyze the binding mode,which established a system for the structure-based development of PDNPA-like compounds targeting Nur77.