A TRIM21-based bioPROTAC highlights the therapeutic benefit of HuR degradation
Alice Fletcher, Dean Clift, Emma de Vries, Sergio Martínez Cuesta, Timothy Malcolm, Francesco Meghini, Raghothama Chaerkady, Junmin Wang, Abby J. Chiang, Shao Huan Samuel Weng, Jonathan Tart, Edmond Wong, Gerard G. Donohoe, Philip B. Rawlins, Euan Gordon, Jonathan D. Taylor, Leo C. James, James Hunt
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.