Covalent Stabilizers of the Interaction Between 14-3-3σ and Estrogen Receptor-α

ACS Medicinal Chemistry Letters 2026 Open access

Read full text
Authors: Rama Jain, Mark Knapp, Sarah E. Kochanek, Adam Lewis, Lynn M. McGregor, Vanja Stojković, Jenny Tang, Tiffany Tsang, Kelly Yan, Aregahegn Yifru, Qingming Zhu, Francesca Fabbiani
+15 more Feng Gu, Andreas O. Frank, John Fuller, Wolfgang Jahnke, Johanna M. Jansen, Jihye Jo, Min Li, Jennifer Lipps, Yipin Lu, Tim Mladenovic, Philippe Piéchon, Phuong Rogemoser, Feng Wang, Shengtian Yang, Colin K. Skepper
DOI: 10.1021/acsmedchemlett.6c00325
Cited by: 1
References: 28

Abstract

Abstract Selective stabilization of complexes formed by the hub protein 14-3-3 represents an emerging mechanism for the modulation of therapeutically relevant targets. In this letter, we describe a hit-finding campaign designed to identify small molecule stabilizers of the interaction between 14-3-3σ and the estrogen receptor alpha (ERα). Four structurally distinct hits were identified and validated using a combination of biochemical assays and biophysical techniques. Ternary complex crystal structures revealed that all four hit compounds form a covalent bond with Cys38 of 14-3-3σ via four different electrophilic warheads. Structure-based optimization of the most promising hit compound 9 led to dramatic improvements in stabilization activity and selectivity that exceeded the complex natural product fusicoccin A.

Fields of Study & Subjects

14-3-3 protein interactions Microbial Natural Products and Biosynthesis Nicotinic Acetylcholine Receptors Study

Publication details

Journal / source
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society (ACS)
Volume
17
Issue
9
Pages
2006–2016
Publication date
17 August 2026
Language
EN