Molecular glue

A molecular glue is a small molecule that induces the interaction between two proteins that do not normally interact.

The most commonly employed molecular glue induces a novel interaction between a substrate receptor of an E3 ubiquitin ligase and a target protein leading to proteolysis of the target.[1] Examples of molecular glues that induce degradation of protein targets include the immunomodulatory imide drug (also known as IMiD; e.g., thalidomide, lenalidomide, pomalidomide), which generate a novel interaction between a substrate (e.g., IKZF1/3, also known as Ikaros/Aiolos) and cereblon, a substrate receptor (also known as DCAF) for Cullin-RING ubiquitin ligase 4 (CRL4).[2][3] They work in a similar manner to PROTAC molecules, bringing about targeted protein degradation. Distinct from PROTAC molecules, molecular glues insert into a naturally occurring PPI interface, with contacts optimized for both the substrate and ligase within the same small molecule entity.[4][5]

The phrase "molecular glue" was coined in 1992 by Stuart Schreiber in reference to the immunophilins.[6]

References
  1. Tian C, Burgess K (January 2021). "PROTAC Compatibilities, Degrading Cell-Surface Receptors, and the Sticky Problem of Finding a Molecular Glue". ChemMedChem. 16 (2): 316–318. doi:10.1002/cmdc.202000683. PMID 33112038. S2CID 225100015.
  2. Petzold, Georg; Fischer, Eric S.; Thomä, Nicolas H. (April 2016). "Structural basis of lenalidomide-induced CK1α degradation by the CRL4CRBN ubiquitin ligase". Nature. 532 (7597): 127–130. doi:10.1038/nature16979.
  3. den Besten W, Lipford JR (August 2020). "Prospecting for molecular glues". Nature Chemical Biology. 16 (11): 1157–1158. doi:10.1038/s41589-020-0620-z. PMID 32747810. S2CID 220947901.
  4. Simonetta KR, Taygerly J, Boyle K, Basham SE, Padovani C, Lou Y, Cummins TJ, Yung SL, von Soly SK, Kayser F, Kuriyan J, Rape M, Cardozo M, Gallop MA, Bence NF, Barsanti PA, Saha A (March 2019). "Prospective discovery of small molecule enhancers of an E3 ligase-substrate interaction". Nature Communications. 10 (1): 1402. Bibcode:2019NatCo..10.1402S. doi:10.1038/s41467-019-09358-9. PMC 6441019. PMID 30926793.
  5. Kozicka, Zuzanna; Thomä, Nicolas Holger (July 2021). "Haven't got a glue: Protein surface variation for the design of molecular glue degraders". Cell Chemical Biology. 28 (7): 1032–1047. doi:10.1016/j.chembiol.2021.04.009.
  6. Schreiber, Stuart L. (August 1992). "Immunophilin-sensitive protein phosphatase action in cell signaling pathways". Cell. 70 (3): 365–368. doi:10.1016/0092-8674(92)90158-9. ISSN 0092-8674.


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