4.8 Article

Bridged Proteolysis Targeting Chimera (PROTAC) Enables Degradation of Undruggable Targets

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JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
卷 144, 期 49, 页码 22622-22632

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AMER CHEMICAL SOC
DOI: 10.1021/jacs.2c09255

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资金

  1. National Institutes of Health [1S10OD025132, 1S10OD028504]
  2. U.S. National Institutes of Health [R01CA218600, R01CA230854, R01CA260666, R01CA268384, R01CA268519]
  3. National Institute of General Medical Sciences (NIGMS) [T32GM062754]

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Proteolysis Targeting Chimeras (PROTACs) are effective for degrading disease-causing proteins. A novel approach called bridged PROTAC has been developed to target undruggable proteins by bringing the protein complex close to an E3 ubiquitin ligase using a small molecule binder of the target protein's binding partner. This approach has led to the discovery of MS28, the first-in-class degrader of cyclin D1, and it shows superior degradation efficiency and proliferation inhibition compared to CDK4/6 inhibitors and degraders. The bridged PROTAC strategy could serve as a generalizable platform for targeting undruggable proteins.
Proteolysis Targeting Chimeras (PROTACs) are attractive therapeutic modalities for degrading disease-causing proteins. While many PROTACs have been developed for numerous protein targets, current small-molecule PROTAC approaches cannot target undruggable proteins that do not have small-molecule binders. Here, we present a novel PROTAC approach, termed bridged PROTAC, which utilizes a small molecule binder of the target protein's binding partner to recruit the protein complex into close proximity with an E3 ubiquitin ligase to target undruggable proteins. Applying this bridged PROTAC strategy, we discovered MS28, the first-in-class degrader of cyclin D1, which lacks a small-molecule binder. MS28 effectively degrades cyclin D1, with faster degradation kinetics and superior degradation efficiency than CDK4/6, through recruiting the CDK4/6-cyclin D1 complex to the von Hippel-Lindau E3 ligase. MS28 also suppressed the proliferation of cancer cells more effectively than CDK4/6 inhibitors and degraders. Altogether, the bridged PROTAC strategy could provide a generalizable platform for targeting undruggable proteins.

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