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Molecular Glues Criteria

Molecular glues are small molecules that exert a biological effect by inducing new protein-protein associations 1. The induced interaction can lead to homo- or hetero-dimerization or oligomerization of the proteins involved. The binding of a small-molecule glue to one protein can induce a new protein-protein interaction through different mechanisms. Binding to a pocket on one protein may create a new protein surface at the pocket, creating complementarity to the surface of a new binding partner. The glue is bound at the interface between the interacting proteins in a ternary or higher-order complex and stabilizes their interaction (Figure 1). Alternatively, binding of the small molecule to one protein may lead to an allosteric conformational change in the protein that creates and stabilizes a new surface for new protein-protein interactions remote from the small molecule binding site. Examples of molecular glues include immune-modulatory compounds such as Cyclosporin A, Rapamycin and other binders of the protein FKBP12, and microtubule-stabilising compounds such as Taxol and discodermalide 1. The criteria for assessing molecular glues as chemical tools parallel those for chemical probes, assessing for binding of both targets 1. A recent review from Hartung et. al. also set the criteria for correct use of Degraders as chemical Probes 3.

Molecular glue degraders are a subset of molecular glues that induce the interaction of an E3 ubiquitin ligase or other protein degradation-effecting complex with a new protein target 2 . The neo-substrate interaction induced by the molecular glue leads to tagging of the target protein, for example by poly-ubiquitination in the case of an E3 ligase, and triggers degradation of the protein by the cell’s proteasomal or autophagic machinery. (Figure 2). Examples of small molecule glue degraders that recruit new proteins to interact with E3 ligases include thalidomide derivatives and indisulam1,2.

The criteria for assessing molecular glue degraders as chemical tools parallel those suggested for the larger, bifunctional PROTAC inducers of degradation.

Molecular Glues listed on the Chemical Probe Portal can be found here.

1. S. Schreiber (2021) Cell, 184, 3-9. (DOI: 10.1016/j.cell.2020.12.020)
2. R. Chopra, A. Sadok, I. Collins (2019) Drug Discov. Today Technol., 31, 5-13. (DOI: 10.1016/j.ddtec.2019.02.002)
3. I.V. Hartung et al. (2023) J Med Chem (DOI: 10.1021/acs.jmedchem.3c00550)

Molecular Glue Degrader
  • Evidence of binding to E3-ligase (CRBN, VHL, etc) or other non-E3 degradation effector complexes
  • Optional: in vitro complex formation between E3 component protein, molecular glue and target protein
Control Compounds def
  • Derivative of the molecular glue that is non-binding to E3 ligase or another effector complex
  • Inhibitor or another non-degrading modulator of the degraded target
Off-target activity
  • Optional: in vitro pharmacology screening against potential off-targets
In-cell validation
  • Evidence and quantification of target engagement and degradation
  • DC50 and Dmax values determined
  • Time course for degradation defined
  • Evidence of E3, ubiquitin and proteasome-dependence; or dependence on other effector pathways relevant to degradation mechanism
  • Phenotype is degradation dependent (comparison to non-degrading derivative)
Off target activity in cells
  • Evidence of in-cell target selectivity
    • e.g. degradation profile measured by MS / proteomics
    • e.g. measurement of off-target engagement / inhibition / depletion
  • Optional: Orthogonal probe (active but different chemotype)
Evidence of cellular permeability Demonstrable by steps above