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TARGETED PROTEIN DEGRADATION

Molecular glue concept solidifies

Nature Chemical Biology volume 16, pages 2–3 (2020)Cite this article

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Molecular-glue-mediated proximity-induced degradation now allows unprecedented therapeutic targeting of previously undruggable proteins. Structures showing how aryl-sulfonamides mediate recruitment of the splicing factor RBM39 to the E3 CRL4DCAF15 broaden the mechanistic principles by which molecular glues target ubiquitylation.

Targeted degradation is a new frontier for therapeutics for proteins lacking enzymatic function. There are three broad modalities by which small molecules have been shown to adjoin an E3 ligase with a heterologous target protein to promote its ubiquitylation and subsequent degradation. In heterobifunctional PROTACs, two small molecules independently binding to a target protein and to an E3 ligase, such as a cullin-RING ligase (CRL), are connected by a chemical linker. By contrast, allosteric modulators may alter the structure of an E3 or target to promote their non-native interactions. Finally, molecular glues bind in crevices at the surfaces of E3s and/or target proteins to establish complementarity, thereby acting like adhesives bringing the two entities together. Molecular glues, first described for plant hormones such as auxin, gluing together E3 ligase CRL1TIR1 and transcription factor targets1, are particularly attractive for drug development because of their relatively small size and propensity for structure-based elaboration. The extension to therapeutics was validated by immunomodulatory drugs (IMiDs) related to thalidomide mediating neosubstrate interactions with E3 ligase CRL4CRBN (refs. 2,3,4). Several new studies5,6,7 showing how the investigational drug aryl-sulfonamide drugs indisulam, E7820, and tasisulum act as molecular glues now provide structural and mechanistic insights that greatly extend our understanding of the principles and opportunities for targeting.

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Fig. 1: Mechanism of molecular glue induced substrate recruitment to CRL4.

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  1. Department of Molecular Machines and Signaling, Max Planck Institute of Biochemistry, Martinsried, Germany

    Kheewoong Baek & Brenda A. Schulman

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  1. Kheewoong Baek
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  2. Brenda A. Schulman
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Correspondence to Brenda A. Schulman.

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Baek, K., Schulman, B.A. Molecular glue concept solidifies. Nat Chem Biol 16, 2–3 (2020). https://doi.org/10.1038/s41589-019-0414-3

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