A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation

Alice Fletcher (), Dean Clift, Emma Vries, Sergio Martinez Cuesta, Timothy Malcolm, Francesco Meghini, Raghothama Chaerkady, Junmin Wang, Abby Chiang, Shao Huan Samuel Weng, Jonathan Tart, Edmond Wong, Gerard Donohoe, Philip Rawlins, Euan Gordon, Jonathan D. Taylor, Leo James and James Hunt ()
Additional contact information
Alice Fletcher: R&D, AstraZeneca
Dean Clift: Francis Crick Avenue, Cambridge Biomedical Campus
Emma Vries: R&D, AstraZeneca
Sergio Martinez Cuesta: Discovery Sciences, R&D, AstraZeneca
Timothy Malcolm: R&D, AstraZeneca
Francesco Meghini: R&D, AstraZeneca
Raghothama Chaerkady: Discovery Sciences, R&D, AstraZeneca
Junmin Wang: Discovery Sciences, R&D, AstraZeneca
Abby Chiang: Discovery Sciences, R&D, AstraZeneca
Shao Huan Samuel Weng: Discovery Sciences, R&D, AstraZeneca
Jonathan Tart: Discovery Sciences, R&D, AstraZeneca
Edmond Wong: R&D, AstraZeneca
Gerard Donohoe: R&D, AstraZeneca
Philip Rawlins: Discovery Sciences, R&D, AstraZeneca
Euan Gordon: Discovery Sciences, R&D, AstraZeneca
Jonathan D. Taylor: R&D, AstraZeneca
Leo James: Francis Crick Avenue, Cambridge Biomedical Campus
James Hunt: R&D, AstraZeneca

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract Human antigen R (HuR) is a ubiquitously expressed RNA-binding protein, which functions as an RNA regulator. Overexpression of HuR correlates with high grade tumours and poor patient prognosis, implicating it as an attractive therapeutic target. However, an effective small molecule antagonist to HuR for clinical use remains elusive. Here, a single domain antibody (VHH) that binds HuR with low nanomolar affinity was identified and shown to inhibit HuR binding to RNA. This VHH was used to engineer a TRIM21-based biological PROTAC (bioPROTAC) that could degrade endogenous HuR. Significantly, HuR degradation reverses the tumour-promoting properties of cancer cells in vivo by altering the HuR-regulated proteome, highlighting the benefit of HuR degradation and paving the way for the development of HuR-degrading therapeutics. These observations have broader implications for degrading intractable therapeutic targets, with bioPROTACs presenting a unique opportunity to explore targeted-protein degradation through a modular approach.

Date: 2023
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DOI: 10.1038/s41467-023-42546-2

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