Design,Synthesis,and Biological Evaluation Of Anti-cancer Agents Targeting Nuclear Receptors Nur77 And RXRα

Cancer,a malignant disease,has endangered public health in China.Nuclear receptor RXRa and Nur7 7 play an important roles in the growth,proliferation and apoptosis of cancer cells.Our early studies(Science(2000)[1]and Cell(2004)[2])have shed light on the apoptoic role of Nur77:with external stimuli,Nur77 could translocates from the nucleus to mitochondria,where it interacted with Bcl-2 and induced cytochrome c release and apoptosis.Our recent publication in Development Cell(2020)[3]reported a newly anti-caner function of RXRα:On the onset of mitosis in cancer cells,RXRa is phosphorylated by Cdk1,resulting in its translocation to the centrosome,where it interacts with PLK1 to promote centrosome maturation and mitotic progression.Targeting RXRa and Nur77 to regulate their nongenomic anticancer pathway is a promising strategy for cancer therapy.Design,synthesis,and anti-cancer evaluation of bis-indole derivatives targeted Nur77:small molecules targeting Nur77 and regulating Nur77-Bcl-2 nongenomic apoptosis pathway were rarely reported.Our goal is to identify such small molecules.Three series of novel aryl-indole derivatives were designed,synthesized,and evaluated.Our efforts identified P-DIM-11,P-DIM-13,P-DIM-23,and P-DIM-26 that bind Nur77 and display good anti-cancer activity.To optimize aryl-bisindolemethyl cation C-DIM1,which strongly induced cancer cell apoptosis in Nur77-Bcl-2 depenedant pathway[Kd(Nur77-LBD)=170 nM,IC50(MDA-MB-231)=0.70±0.11 μM],75 aryl-bisindolemethyl cation derivatives were designed,synthesized and evaluated.C-DIM-2,CDIM-B5,C-DIM-A11,C-DIM-B6,and C-DIM-B17,which display high binding affinity with Nur77(Kd<100 nM)and potent inhibitory activity against breast cancer and colon cancer(MDA-MB-231 and HCT116,IC50<100 nM),were obtianed.In pharmacokinetic studies,C-DIM-2 was found to be a promising compounds.Design,synthesis,and anti-mitotic evaluation of acylhydrazones-based derivatives targeted RXRα:Recently XS-060 was identified to be a hit molecule that binds to RXRa co-regulatory binding site and selectively inhibits RXRα-PLK1 dependent mitotic process and catastrophe in cancer cells.In this study,32 Acylhydrazones-based compounds were designed,synthesized,and evaluated.As a result we obtained a potent compound XS60-B10 that exhibited good anticancer activity(HepG2,IC50=3.89±0.45 μM)and cancer cell selectivity(LO2,IC50>50 μM),providing a new stragegy for developing of highly efficacy and low toxic lead compounds targeting RXRα.