期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 5, 页码 3894-3912出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01730
关键词
-
资金
- University of Illinois
- Cancer Center at Illinois (CCIL)
- NIH Chemistry-Biology Interface Training Program [T32-GM136629]
- NCI [F99-CA253731]
Approximately 75% of breast cancers are ER alpha-positive, and current therapeutic strategies targeting ER alpha have limitations. A recent study identified a compound called ErSO that induces ER alpha-dependent cancer cell death through a unique mechanism and shows potential as a new drug. Modified versions of ErSO were constructed and one variant, ErSO-DFP, demonstrated enhanced selectivity for ER alpha-positive cancer cells and good tolerability in rodents. ErSO-DFP and related compounds may represent a novel class of treatments for ER alpha-positive cancers.
Approximately 75% of breast cancers are estrogen receptor alpha-positive (ER alpha+), and targeting ER alpha directly with ER alpha antagonists/degraders or indirectly with aromatase inhibitors is a successful therapeutic strategy. However, such treatments are rarely curative and development of resistance is universal. We recently reported ErSO, a compound that induces ER alpha-dependent cancer cell death through a mechanism distinct from clinically approved ER alpha drugs, via hyperactivation of the anticipatory unfolded protein response. ErSO has remarkable tumor-eradicative activity in multiple ER alpha+ tumor models. While ErSO has promise as a new drug, it has effects on ER alpha-negative (ER alpha-) cells in certain contexts. Herein, we construct modified versions of ErSO and identify variants with enhanced differential activity between ER alpha+ and ER alpha- cells. We report ErSO-DFP, a compound that maintains antitumor efficacy, has enhanced selectivity for ER alpha+ cancer cells, and is well tolerated in rodents. ErSO-DFP and related compounds represent an intriguing new class for the treatment of ER alpha+ cancers.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据