Discovery of inhibitors for nuclear receptor functions with multiple mechanisms

点击翻译按钮获取中文摘要

Nuclear receptors (NRs) are ligand-dependent transcription factors which regulate the expression of responsive genes and thereby affect diverse diseases. Once an agonist activates the NR, recruitment of additional coactivator proteins is essential for transcription. NRs modulators often possess issues, including cross reactivity with other NRs, and existence of drug-resistant cancers. To overcome these issues, I aimed multiple inhibitions of NRs functions. First, five kinds of NRs modulators with different skeletons from physiological ligands were generated. Second, non-peptide coactivator mimetics for a NR were generated. Now, hybrid molecules consisting of modulators for NRs linked to coactivator mimetics are being prepared. On the other hand, we developed a method that induces selective degradation of target proteins by small molecules (protein knockdown). Utilizing this method, a compound that inhibits a NR function with multiple mechanisms (antagonism and decrease of the NR) was generated.