Design,Synthesis,and Biological Activity Studies Of ERR? Small Molecule Reverse Agonists

Breast cancer is one of the most common malignancies in women,a serious threat to the women's physical and mental health all over the world.In the field of breast cancer treatment,molecular targeted therapy is one of the most active research fields in recent years.Among them,Estrogen-related receptor alpha(ERRa)is the most promising target for treating breast cancer.ERRa not only promotes the growth and invasion of hormone-dependent and hormone-independent breast cancer,but also promotes vascular smooth muscle cell proliferation,endothelial microtubule formation and tumor angiogenesis,indicating that ERRa is a negative energy regulator of breast cancer disease and a novel drug target for treating breast cancer,which provides a new direction for the treatment of breast cancer.Compared with the traditional breast cancer treatment drugs,high active and selective ERRa target therapy drugs have small side effects,good therapeutic effect.A large number of studies have indicated that ERRa small molecule reverse agonists are the most promising molecules to be targeted drugs for the treatment of breast cancer drugs.At present,the synthesized and reported ERRa small molecule reverse agonists are divided into four categories:XCT-790,N-arylindole,thiazolidinedione,1-phenyl-4-benzoyl-Hydrogen-triazoles.Although these small molecule reverse agonists have led to a certain advance in the ERRa targeted therapeutic treatment of breast cancer,the lack of activity and specificity of these reported targeted drug molecules has not yet reached the clinical standard for the treatment of breast cancer.Due to the limited number of small interferon agonists currently reported,it has brought great difficulties and obstacles to the research in this field.Due to the limited number of small interferon agonists,the study of this field has been hampered.However,in the bioactivity test of the urea-based tyrosine tyrosine phosphatase 1B(PTP1B)inhibitor(compound 24)previously synthesized by our team,it was found that the compound exhibited activity against the PTP1B target while exhibiting the activity against ERRa target.PTP1B also plays a negative energy role in human cancer disease,which has led us to an idea:to explore and find a group of compounds that play a reverse agitation effect on ERRa while suppressing the inhibitory effect of PTP1B.In this paper,sybyl and pymol software were used to summarize the characteristics and rules of the interaction between the small molecule reverse agonists and ERRa as well as the reported inhibitors and PTP1B,and we screened and synthesized 14 compound molecules(P1-P14)containing potentials double target actions.We have made a basis for the synthesis of these compounds,the study of the structure-activity relationship,and the bioactivity test(which is still underway),for further structural optimization to achieve better activity of the compound molecules.