近日，美国基因技术公司Ciara Metcalfe研究团队发现治疗性配体（ER）通过影响雌激素受体的移动来发挥拮抗功能。该研究于2019年8月9日发表于国际一流学术期刊《细胞》上。

研究人员发现对ER降解的优化并不能保证乳腺癌细胞中完全的ER拮抗作用；ER“降解剂”表现出一系列转录活性和抗增殖潜力。从机理上讲，研究人员发现氟维司群一类的拮抗剂不是通过清除ER来抑制其转录活性，而是通过显著减慢ER的核内迁移率来实现。ER这种转变的增加是其移动受阻的结果。这些发现提供了概念性证明，即通过小分子干扰转录因子的移动性可以让这一类挑战性的靶标变得能够治疗。

研究人员表示，即使在获得对内分泌药物的抗性后，雌激素受体阳性（ER +）的乳腺癌仍经常依赖于ER信号，这促进了ER拮抗剂优化的发展。氟维司群（Fulvestrant）在批准的ER治疗药物中是独特的，因其具有完全ER拮抗的能力，这被认为是通过降解ER来实现的。氟维司群的临床使用受到不良物理化学特征的限制，这促进了对产生具有改善药物特性的ER降解物的尝试。

附：英文原文

Title: Therapeutic Ligands Antagonize Estrogen Receptor Function by Impairing Its Mobility

Author: Jane Guan, Wei Zhou, Marc Hafner, Lori S. Friedman, Anneleen Daemen, Ciara Metcalfe

Issue&Volume: Volume 178 Issue 4

Abstract: Estrogen receptor-positive (ER +) breast cancers frequently remain dependent on ER signaling even after acquiring resistance to endocrine agents, prompting the development of optimized ER antagonists. Fulvestrant is unique among approved ER therapeutics due to its capacity for full ER antagonism, thought to be achieved through ER degradation. The clinical potential of fulvestrant is limited by poor physicochemical features, spurring attempts to generate ER degraders with improved drug-like properties. We show that optimization of ER degradation does not guarantee full ER antagonism in breast cancer cells; ER “degraders” exhibit a spectrum of transcriptional activities and anti-proliferative potential. Mechanistically, we find that fulvestrant-like antagonists suppress ER transcriptional activity not by ER elimination, but by markedly slowing the intra-nuclear mobility of ER. Increased ER turnover occurs as a consequence of ER immobilization. These findings provide proof-of-concept that small molecule perturbation of transcription factor mobility may enable therapeutic targeting of this challenging target class.

DOI: https://doi.org/10.1016/j.cell.2019.06.026

Source: https://www.cell.com/cell/fulltext/S0092-8674(19)30689-0