Description of Molecular Glue

A molecular glue is a small-molecule drug that acts as a double-sided adhesive tape. One side sticks to a specific E3 ubiquitin ligase (the "waste disposal tagger" in the cell), and the other side sticks to a disease-related target protein (the "waste"). The formation of the E3-molecular glue-Protein ternary complex brings the E3 ligase and target protein into proximity, initiating target protein ubiquitination and subsequent proteasomal degradation. Driven by their small-molecule drug-likeness, potency in degrading and the potential to expand druggable targets, molecular glues are the subject of intense interest from the worldwide pharmaceutical industry. They are not simply a new chemistry but a fundamentally new therapeutic modality.

Origin and Development of Molecular Glue

The history of molecular glues is closely linked to that of thalidomide. Sold in the 1950s as a sedative, thalidomide was very quickly banned from the market for its teratogenicity. Only half a century later were scientists able to elucidate its mechanism of action: thalidomide is not a classical inhibitor, but a molecular glue which causes the proximity between the E3 ubiquitin ligase and the transcription factors IKZF1/3, thereby causing degradation of the latter. This historic discovery opened the door to an entirely new goldmine of drug targets. Subsequently, more molecular glue drugs have been developed and successfully brought to market. Beyond CRBN, molecular glues targeting other E3 ligases have also entered clinical research stages, holding promise as potential breakthrough therapies for incurable diseases.

Fig. 1. Molecular mechanism of thalidomide activity (Shaobing Gao, et al. 2020)

Screening for Molecular Glue

Despite a number of interesting molecular glues being discovered early on through phenotypic screening or by fortunate accidents, a general approach that could rationally and directly screen for such molecules in large compound libraries has been missing. Daniel J. Blair and colleagues designed a so-called "function-first" direct screening approach. Instead of having to purify compounds, they were able to sensitively detect the unique kinetic profiles of small-molecule-stabilized "protein–protein–ligand" ternary complexes formed in the unpurified (tens of thousands of nanoliter-scale) reaction mixtures using affinity selection mass spectrometry (ASMS) in order to directly and rationally identify molecular glues.

Fig. 2. Principles of ASMS screening for molecular glues (Hu, Maowei, et al. 2025)

To validate this theory, researchers used two known molecular glue systems to test the stability of the ASMS assay. For the CRBN–GSPT1 pair, when both were present, the molecular glue SJ6986 (a GSPT1 glue) generated an ASMS signal about twice the size than when CRBN was present alone, while the compound CC-220, which only binds CRBN and does not recruit GSPT1, did not show enrichment. Similar findings were seen with the molecular glue Daratonrasib in a Cyclophilin A–KRAS system, further showing ASMS's reliability.

Fig. 3. ASMS screening Stability Validation (Hu, Maowei, et al. 2025)

Hu et al. successfully utilized this method to discover novel molecular glues targeting the CRBN-LCK target and validated their functions. First, they used 16 chemical building blocks with CRBN binding modules to build a molecular glue library via chemical reaction. Then, the library was screened to identify molecular glues that could bridge the CRBN-LCK protein pair. The first screening used the CRBN-LCK complex to screen for the first time, and the second screening used CRBN-LCK, CRBN, and LCK alone to screen to see whether the enrichment was specifically dependent on the ternary complex. In the end, they successfully identified 17-21 containing an indole structure. It was confirmed by Alphascreen assays and cell experiments that 17-19 could induce the degradation of LCK.

Fig. 4. Screening of CRNB-LCK target molecules (Hu, Maowei, et al. 2025)

Advantages of Molecular Glue

• Targeting the "Undruggable"
• High Potency and Efficacy
• Favorable Drug-like Properties
• Enhanced Selectivity

Recommended Product

Protheragen is dedicated to cutting-edge research and development, providing molecular glue active pharmaceutical ingredients (APIs) to global partners with reliable quality and stable supply. If you are interested in our products, please contact us.