Linking Chemical Fragments, "Gluing" Protein Complexes, Connecting across Cultures.

This invited Team Profile was created by Michelle Arkin and Adam Renslo from the University of California, San Francisco in the USA and Luc Brunsveld and Christian Ottmann from the Eindhoven University of Technology in the Netherlands. They recently published an article on designing molecular glues for the 14-3-3/estrogen receptor (ER) protein-protein interaction (PPI). Molecular glues increase the binding between two proteins by binding at the PPI interface. While they hold exciting promise to induce new biology and treat disease, systematic approaches to discover glues are just becoming available. Fragment-based drug discovery has been used to discover inhibitors of PPI; here, the team demonstrated a fragment discovery and linking strategy to create a new molecular glue for 14-3-3/ER, an anticancer target. "From Tethered to Freestanding Stabilizers of 14-3-3 Protein-Protein Interactions though Fragment Linking", E. J. Visser, P. Jaishankar, E. Sijbesma, M. A. M. Pennings, E. M. F. Vandenboorn, X. Guillory, R. J. Neitz, J. Morrow, S. Dutta, A. R. Renslo, L. Brunsveld, M. R. Arkin, C. Ottmann, Angew. Chem. Int. Ed. 2023, 62, e202308004.