Structure-based Design And Development Of Csn-B Derivatives

Nuclear receptors(NR)are a large family of ligand-activated transcription factors,which are involved in complex biological processes through interacting with other co-regulatory factors or proteins to perform transcriptional functions and to participate in cellular signaling pathways.The dysfunction of NR activities is associated with a range of diseases,including diabetes,Alzheimer’s disease,cancer and cardiovascular disease.NRs are considered as the important drug targets for diseases.Classified in the nuclear receptor subfamily NR4A,Nur77 is as orphan nuclear receptors with no known endogenous ligands.Nur77 is widely expressed across various tissues,such as thyroid,adrenal gland,liver,pituitarium,thymus,ovary,testis,prostate,muscle,developing nervous system among others.The transcriptional activity of Nur77 is activated through alterations in gene expression,post-translational modifications and interactions with coregulatory proteins.Nur77 is involved in complex biological processes including inflammation,hepatic glucose metabolism and programmed cell death,and it is also the target of various drugs.Previous studies showed that Csn-B specifically bound to the LBD(Ligand binding domain)of Nur77 and enhanced Nur77-dependent transactivational activity on target gene transcription.With the increased expression of Nur77,Csn-B could enhance gluconeogenesis in the mouse liver,induce apoptosis and promote the translocation of Nur77 to the cytoplasm to inhibit xenograft tumor growth.However,although there were reports about Csn-B regulation of Nur77 function,most of these studies were about the interaction between Csn-B and Nur77 in terms of physiological functions.Up to date,no crystal structure of Nur77-Csn-B complex was determined,which prevented the knowledge-based improvement of Csn-B for drug development.In this thesis,we designed and synthesized a series of derivatives of Csn-B and determined the complex crystal structures of Nur77 LBD with Csn-B and its derivative Csn-B 2C.This work provided the structure-based improvement of Csn-B and produced new lead compounds for the development of therapeutic agents to treat cancer and metabolic diseases.