Covalent Stabilizers of the Interaction Between 14-3-3σand Estrogen Receptor-α
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.
Authors
- Andreas O. Frank (ORCID: https://orcid.org/0000-0002-2330-3974)
- Aregahegn Yifru
- Shengtian Yang (ORCID: https://orcid.org/0000-0003-0255-0471)
- Lynn M. McGregor (ORCID: https://orcid.org/0000-0003-4310-2384)
- Colin K. Skepper (ORCID: https://orcid.org/0000-0002-6771-2024)
- Jennifer Lipps
- Feng Wang (ORCID: https://orcid.org/0000-0002-4322-2127)
- Sarah E. Kochanek (ORCID: https://orcid.org/0000-0001-6213-8476)
- Johanna M. Jansen (ORCID: https://orcid.org/0000-0003-3937-6243)
- Wolfgang Jahnke (ORCID: https://orcid.org/0000-0002-7003-3305)
- Tiffany Tsang
- Tim Mladenovic (ORCID: https://orcid.org/0000-0003-0710-039X)
- Vanja Stojković (ORCID: https://orcid.org/0000-0002-9885-3428)
- Phuong Rogemoser
- Min Li (ORCID: https://orcid.org/0000-0002-3971-9130)
- Feng Gu (ORCID: https://orcid.org/0000-0002-0045-4403)
- Yipin Lu
- Rama Jain
- Philippe Piéchon
- Qingming Zhu
- Mark Knapp
- John Fuller
- Francesca Fabbiani
- Jenny Tang
- Jihye Jo
- Kelly Yan
- Adam Lewis
Institutions
- Novartis (Switzerland) (CH)
- Novartis (China) (CN)
Publication Details
- Journal
- ACS Medicinal Chemistry Letters
- Published
- 2026-08-17
- DOI
- https://doi.org/10.1021/acsmedchemlett.6c00325
- Primary Topic
- 14-3-3 protein interactions
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Novartis