A groundbreaking discovery has been made by researchers at the University of Crete, the University of California San Francisco (UCSF), and Eindhoven University of Technology.

The research team led by Associate Professor Konstantinos Neochoritis from the UoC Department of Chemistry, in collaboration with Professor Michelle Arkin (UCSF) and Professor Christian Ottmann (TU Eindhoven), has developed an innovative method for discovering molecular glues that stabilize the 14-3-3/ERα protein complex. This breakthrough holds immediate potential for treating breast cancer that has developed resistance to endocrine therapy.

The study’s findings, published in the prestigious journal Nature Communications, mark a new era in drug design targeting protein–protein interactions (PPIs), which remain some of the most challenging targets in pharmaceutical chemistry.

What Are Molecular Glues?
Molecular glues are small organic molecules that act as “chemical connectors” between two proteins, enhancing and stabilizing their natural interaction. In this case, the goal was to strengthen the interaction between the regulatory protein 14-3-3 and the hormone receptor protein ERα—a strategy that could suppress ERα’s transcriptional activity even in cancer cells that have developed resistance to conventional therapies.

A Novel Synthetic Approach
The synthesis of these molecules was achieved through a flexible and highly efficient methodology based on multicomponent reactions (MCRs). This approach enabled the rapid generation and screening of dozens of structurally diverse compounds. Using structural and biophysical analyses, the researchers were able to elucidate the binding mechanisms of the molecular glues and identify the most potent candidates.

Implications for Breast Cancer Treatment
This approach offers a promising alternative for tackling forms of breast cancer that no longer respond to existing endocrine treatments, providing hope for new, targeted pharmacological interventions.

For further information, you can access the full publication in Nature Communications (DOI: 10.1038/s41467-025-61176-4).