Druglike Molecular Degraders of the Oncogenic RNA-Binding Protein HuR.

Hu antigen R (HuR), also known as ELAVL1, is an RNA-binding protein (RBP) that plays a pivotal role in promoting oncogene expression by stabilizing oncogenic mRNAs. Elevated cytoplasmic levels of HuR are strongly associated with critical processes in breast cancer progression, including enhanced proliferation, survival, and metastasis. Targeting HuR presents a promising therapeutic strategy for aggressive subtypes of breast cancer. In this study, we developed small molecule degraders using both Molecular glues and Proteolysis TArgeting Chimera (PROTAC) technologies. The most effective degraders significantly reduced HuR levels in breast cancer cell lines, exhibiting a biphasic degradation profile due to dual-pocket engagement. This resulted in decreased expression of HuR-associated mRNAs and inhibition of breast cancer cellular phenotypes in both 2D and 3D spheroid cancer models. The lead degrader met all druglikeness criteria across the evaluated models. With the increasing interest in molecular glues and PROTACs within pharmaceutical development, targeted protein degradation is emerging as a powerful strategy for addressing previously undruggable proteins. These findings underscore the potential of molecular glues and PROTACs to navigate the challenges of targeting structurally dynamic RBPs such as HuR. The development of these degraders offers a promising therapeutic pathway with significant implications for cancer and other RNA-driven diseases.