Design, synthesis, and biological evaluation of novel PROTACs compounds with good ERα degradation ability

Abstract

A series of ER-PROTACs compounds were designed, synthesized and tested for their ability to degrade estrogen receptor proteins and exhibit Human breast cancer cells (MCF-7) inhibition activity. Molecular docking simulations were performed using Discovery studio. Among these compounds, QDE-003-W had the highest estrogen receptor protein degradation ability and cellular activity, with a DC₅₀ value of 95 nM, for estrogen receptor protein degradation and an IC₅₀ value of 30.2 nM for cellular activity. Furthermore, the molecular docking study revealed that the biological activity of QDE-003-W depended on its suitable linker length, which gave us some reference significance for the study of ER-PROTACs. And compared with fulvestrant, QDE-003-W exhibited more favorable pharmacokinetic (PK) characteristics. No significant adverse side effects were observed under the administration protocol, which indicates that the tested mice had excellent tolerance to both the administration method and the dosage. Such favorable PK characteristics and safety features further enhance the prospects of QDE-003-W as a viable candidate for subsequent preclinical and clinical development.