11SG

Covalent stabilizer compound 11 for the interaction between 14-3-3 sigma and Estrogen receptor-alpha peptide

This is a non-PDB format compatible entry.

Summary for 11SG

• Entry DOI: 10.2210/pdb11sg/pdb
• Descriptor: 14-3-3 protein sigma, Estrogen receptor, (2S)-2-(1-acetylpiperidin-4-yl)-2-(4-chlorophenyl)-N-{2-[(Z)-iminomethyl]pyrimidin-5-yl}acetamide, ... (4 entities in total)
• Functional Keywords: 14-3-3, adapter, phosphoserine, phosphothreonine, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 60518.11

Authors

Knapp, M.S.,Tang, J.Y. (deposition date: 2026-03-11, release date: 2026-08-26, Last modification date: 2026-09-30)

Primary citation

Jain, R.,Knapp, M.,Kochanek, S.E.,Lewis, A.,McGregor, L.M.,Stojkovic, V.,Tang, J.,Tsang, T.,Yan, K.,Yifru, A.,Zhu, Q.,Fabbiani, F.,Feng, G.,Frank, A.O.,Fuller, J.,Jahnke, W.,Jansen, J.M.,Jo, J.,Li, M.,Lipps, J.,Lu, Y.,Mladenovic, T.,Piechon, P.,Rogemoser, P.,Wang, F.,Yang, S.,Skepper, C.K.
Covalent Stabilizers of the Interaction Between 14-3-3 sigma and Estrogen Receptor‐ alpha.
Acs Med.Chem.Lett., 17:2006-2016, 2026

PubMed 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 led to dramatic improvements in stabilization activity and selectivity that exceeded the complex natural product fusicoccin A.

PubMed: 42741630
DOI: 10.1021/acsmedchemlett.6c00325

Experimental method

X-RAY DIFFRACTION (2.6 Å)