Discovery of inhibitors for nuclear receptor functions with multiple mechanisms

核受体是一种依赖配体的转录因子，它调节应答基因的表达，从而影响多种疾病。一旦激动剂激活NR，额外的辅激活蛋白的募集对于转录是必不可少的。nrrs调节剂通常具有问题，包括与其他nrrs的交叉反应性，以及耐药癌症的存在。为了克服这些问题，我瞄准了对nr功能的多重抑制。首先，从生理配体中合成了5种不同骨架的nr调节剂。其次，生成了NR的非肽共激活物模拟物。现在，由与辅激活剂模拟物连接的nr调节剂组成的杂交分子正在制备中。另一方面，我们开发了一种通过小分子诱导目标蛋白选择性降解的方法（蛋白敲低）。利用这种方法，生成了一种通过多种机制（拮抗和减少NR）抑制NR功能的化合物。

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.