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