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

Yan Xiong, Yue Zhong, Hyerin Yim, Xiaobao Yang, Kwang Su Park, Ling Xie, Poulikos I. Poulikakos, Xiaoran Han, Yue Xiong, Xian Chen, Jing Liu, Jian Jin

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)22622-22632
Number of pages11
JournalJournal of the American Chemical Society
Issue number49
StatePublished - 14 Dec 2022


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