Molecular Glues

What are Molecular Glues?

Molecular Glues are small molecules that achieve targeted protein degradation by bringing about dimerization of target proteins with ubiquitin E3 ligases. This "degradation-by-dimerization" effect may occur either by direct binding interactions between an E3 ligase and the protein of interest, with the small molecule at the protein-protein interface. Alternatively binding of the molecular glue leads to allosteric modification of the E3 ligase protein structure, which alters the substrate binding site of the enzyme, preventing it from binding to its native substrate and enabling it to bind to a target protein, which functions as a neosubstrate.

The formation of a ternary complex comprising the E3 ligase, the protein of interest and the small molecule, results in the ubiquitination of the protein of interest triggering its destruction by the proteasome. Following the ubiquitination step, the molecular glue dissociates, freeing it up to form a new protein complex. Molecular glues therefore have a catalytic mode of action, similar to PROTAC Degraders.

Molecular Glues - Mechanism of Action

Figure 1: Schematic showing the mode of action of Molecular Glue Degraders. Molecular glues are protein dimerizers that initiate the formation of a ternary complex between a ubiquitin E3 ligase and a target protein. Binding of the molecular glue to an E3 ligase presents an altered binding epitope preventing the enzyme from binding to its native substrate and enabling ternary complex formation with a different substrate (or neosubstrate), and its subsequent polyubiquitination and degradation by the proteasome.

Types of Molecular Glue

Thalidomide (Cat. No. 0652) is a known compound that acts as a molecular glue, although its mechanism of action has only recently been elucidated. This compound is one of a group known as IMiDs or immunomodulatory imide drugs, which also includes Lenalidomide (Cat. No. 6305) and Pomalidomide (Cat. No. 6302). IMiDs bind to cereblon, the substrate receptor within the CRL4^CRBN E3 ubiquitin ligase and modulate the enzyme's specificity enabling it to bind to and bring about degradation a range of neosubstrates that includes, the transcription factors IKZF3, IKZF1 and SALL4, as well as casein kinase 1 alpha (CK1α) and the translation termination factor G₁ to S Phase Transition 1 (GSPT1).

Sulfonimides are another group of compounds that act as molecular glues. This group includes Indisulam (Cat. No. 6782) and E 7820 (Cat. No. 6785), which promote the degradation of the RNA splicing factor RBM39 by the ubiquitin E3 ligase DCAF15.

Auxin (Cat. No. 6834) is a naturally occurring plant hormone that also acts as a molecular glue, bringing together F-box proteins of the TIR1/AFB family and members of the Aux/IAA transcriptional repressor family.

Uses for Molecular Glues

The IMiDs are used in medicine to treat hematological cancers, particularly multiple myeloma and are currently being investigated for their potential to treat autoimmune disorders, such as systemic lupus erythematosus. From a therapeutic viewpoint molecular glues have the advantage over PROTACs in that they are likely to exhibit more favorable properties for oral administration, owing to the smaller size of the molecular scaffold.

Literature for Molecular Glues

Tocris offers the following scientific literature for Molecular Glues to showcase our products. We invite you to request* your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.

TPD and Induced Proximity Research Product GuideUpdated

This brochure highlights the tools and services available from Bio-Techne to support your Targeted Protein Degradation and Induced Proximity research, including:

• Active Degraders
• TAG Degradation Platform
• Degrader Building Blocks
• Assays for Protein Degradation
• Induced Proximity Tools

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