Moreno Ballesteros et al. introduce a site-resolved strategy combining genetic code expansion and bioorthogonal chemistry to evaluate how ligand binding sites influence targeted protein degradation. T...

Protein-protein interaction (PPI) networks play a central role in many biological processes and thus the possibility of modulating them using small molecules offers several biomedical and biotechnolog...

This study reports the discovery and characterization of novel CRBN molecular glues that selectively induce the proteasomal degradation of the hematopoietic-specific signaling protein VAV1, a key targ...

A major challenge in evaluating the suitability of ∼700 known and putative E3 ligases for target protein degradation (TPD) is the lack of ligase-specific binders. Here, we use genetic code expansion (...

Heterobifunctional small molecules (hSMs) are a rapidly emerging therapeutic modality that induces spatial proximity between biomolecules, such as proteins, by forming a ternary complex. In this study...

In target-based drug discovery, quantification of target engagement is required to build structure–activity relationships and develop a potent clinical candidate. Target engagement data also provides evidence of a drug’s mechanism of action (MoA) which although is not required for approval, can increase the chance of a successful clinical outcome. Consequently, a plethora of assays has been developed to provide information about target engagement on isolated proteins and in cells. These techniques monitor changes in stability, structure, optical properties or mass difference between proteins and their complexes with ligands. They also provide characterization of the compound with thermodynamic, kinetic and structural binding parameters. The diversity of approaches reflects the challenges faced when drugging different protein classes, with each method having advantages, trade-offs and target specificity.

Thalidomide, lenalidomide, and their derivatives mimic glutarimide and aspartimide protein modifications that give rise to a motif recognized by the E3 ligase substrate adapter cereblon (CRBN). These ...

Linkers are traditionally seen as important for PROTAC activity. Here, the authors demonstrate that linker-free PROTACs can outperform traditional designs, marking a paradigm shift in PROTAC developme...