Rama Jain, Mark Knapp, Sarah E Kochanek, Adam Lewis, Lynn M McGregor, Vanja Stojkovic, Jenny Tang, Tiffany Tsang, Kelly Yan, Aregahegn Yifru, Qingming Zhu, Francesca Fabbiani, Gu Feng, Andreas O Frank, John Fuller, Wolfgang Jahnke, Johanna M Jansen, Jihye Jo, Min Li, Jennifer Lipps, Yipin Lu, Tim Mladenovic, Philippe Piechon, Phuong Rogemoser, Feng Wang, Shengtian Yang, Colin K Skepper
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.