HuR Molecular Glue Degrader, MG-HuR2

MG-HuR2 is a cell-permeable, druglike molecular glue that potently degrades the oncogenic RNA-binding protein HuR (DC₅₀ ≈ 5-10 nM in breast cancer cells) by recruiting the RNF126 E3 ligase. MG-HuR2’s strategic advantage lies in a novel dual-engagement mechanism, binding two distinct RNA-binding pockets (P1/P2) on HuR to drive a unique biphasic degradation profile, enabling more comprehensive and sustained target suppression than conventional inhibitors. This degradation cascade effectively downregulates key HuR-target mRNAs, reducing Bcl2 protein levels by up to 88% at a 10 nM concentration. Functionally, this translates to potent inhibition of cancer cell proliferation, induction of apoptosis, and the arrest of 3D spheroid growth. Given its favorable safety profile and precision mechanism, MG-HuR2 emerges as a powerful chemical tool for interrogating RNA biology and a promising therapeutic candidate for HuR-driven cancers.