New Therapeutic Approach Targets Undruggable Protein Driving Aggressive Breast Cancer

In nan conflict against fierce bosom cancer, a erstwhile elusive target is now wrong reach—thanks to a breakthrough from a squad from nan Faculty of Medicine astatine Hebrew University. Dr. Raphael Benhamou and M.Sc. student Liann Kassabri person developed innovative druglike molecules tin of degrading HuR, a cardinal RNA-binding macromolecule that stabilizes oncogenes and fuels crab progression.

HuR (also known arsenic ELAVL1) has agelong been branded "undruggable" owed to its structural elasticity and deficiency of a accepted progressive site. Overexpressed successful galore crab types—particularly bosom cancer—HuR fortifies malignant cells by protecting mRNAs that thrust compartment maturation and survival. "We knew that simply blocking HuR wasn't enough," says Dr. Benhamou. "We needed to destruct it altogether." Strikingly, this elimination led to a 3 to 4 bid of magnitude betterment successful anticancer properties compared to accepted HuR-binding molecules that do not induce degradation.

The investigation squad turned to 2 cutting-edge therapeutic strategies: PROTACs (Proteolysis-Targeting Chimeras) and molecular glues. While some approaches harness nan cell's ain protein-disposal machinery, molecular glues guidelines retired for their mini size, favorable pharmacokinetics, and oral bioavailability—traits prized successful supplier development.

After synthesizing and testing dozens of candidates, 1 compound successful particular—MG-HuR2—emerged arsenic a front-runner. "MG-HuR2 not only met each awesome druglikeness criterion, it demonstrated powerful activity astatine ultra-low concentrations," says Kassabri. In bosom crab compartment lines, MG-HuR2 reduced HuR levels by up to 85%, disrupted nan look of downstream oncogenes for illustration Bcl2 and FOXQ1, and importantly inhibited compartment proliferation, survival, and 3D tumor spheroid growth.

A striking characteristic of these degraders is their biphasic "hook effect." While activity drops disconnected astatine intermediate doses—a known PROTAC quirk—the squad discovered a rebound successful efficacy astatine higher concentrations. This unsocial behavior, not antecedently observed, was further investigated done computational modeling, which revealed that it stems from nan compounds' expertise to prosecute 2 chopped RNA-binding pockets connected HuR. This uncovering whitethorn unfastened caller avenues for targeting different move RNA-binding proteins.

"The degradation shape was unusual," explains Dr. Benhamou. "But alternatively than a flaw, it turned retired to beryllium a clue. Our degraders hindrance astatine aggregate sites, giving them a broader scope and perchance much durable effects."

The implications are profound. Beyond bosom cancer, HuR is implicated successful various malignancies and inflammatory diseases. With MG-HuR2 and its peers, researchers now person a roadmap for processing narcotics against a people of proteins antecedently thought beyond nan scope of modern medicine.

For now, MG-HuR2 represents a promising lead compound and a milestone successful targeted macromolecule degradation. As Dr. Benhamou puts it, "We're not conscionable inhibiting cancer's messages—we're dismantling its messengers." 

Source:

Journal reference:

Kassabri, L. & Benhamou, R. I., (2025). Druglike Molecular Degraders of nan Oncogenic RNA-Binding Protein HuR. JACS Au. doi.org/10.1021/jacsau.5c00551.