Enamine Germany Contributes to New CRBN Reversible Covalency Preprint

Jun 23, 2026

A PROXIDRUGS collaboration explores reversible boron–histidine covalency for CRBN recruitment and targeted protein degradation.

Enamine Germany is pleased to share the new preprint “Reversible covalency reprograms CRBN substrate recruitment and PROTAC-mediated degradation,” produced through a broad academic and industry collaboration within the PROXIDRUGS – Cluster4Future consortium.

The researchers report boronic-acid-based IMiD derivatives, termed Bo-IMiDs, that engage the CRBN E3 ligase through reversible covalent coordination with His353. Structural studies of the resulting complexes indicate formation of a tetrahedral boronate adduct and show how this interaction can enhance CRBN engagement while suppressing canonical IMiD molecular-glue activity and reshaping the CRBN interactome.

When incorporated into BRD4-targeting proteolysis-targeting chimeras (Bo-TACs), the reversible covalent CRBN ligands produced deep and sustained degradation while preserving catalytic turnover. The study points to reversible boron–histidine targeting as a way to modulate E3-ligase function and expand the chemical space available for targeted protein degradation.

The work brings together researchers from Goethe University Frankfurt, the University of Bonn, the University of Antwerp, Technische Universität Darmstadt, Enamine Germany, Enamine Ltd., Enamine PL and Merck Healthcare KGaA. Enamine Germany is proud to have contributed to this collaborative research effort.

This article is a Version 1 preprint posted on Research Square on 23 June 2026 and has not yet been peer reviewed by a journal.

Read the preprint on Research Square (DOI: 10.21203/rs.3.rs-10120177/v1)