Breast Cancer Therapy: Targeting Undruggable Protein
Dismantling CancerS Messengers: New Molecular Glues Target “Undruggable” HuR Protein
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Jerusalem, Israel – In a important breakthrough for cancer therapy, researchers have developed novel molecular glues capable of fully eliminating the HuR protein, a key driver of cancer cell growth and survival. this innovative approach targets HuR, also known as ELAVL1, a protein long considered “undruggable” due to its structural versatility and absence of a conventional active site. The findings, published in JACS Au, offer a new paradigm for developing drugs against challenging protein targets.
The Challenge of HuR: A Master Regulator of Cancer Progression
HuR plays a critical role in cancer by stabilizing messenger RNAs (mRNAs) that promote cell proliferation and survival. Its overexpression is particularly prevalent in aggressive cancers like breast cancer, where it acts as a potent oncogene. traditional therapeutic strategies that merely block HuR’s function have proven insufficient.”We knew that simply blocking HuR wasn’t enough,” explains Dr.R. I. Benhamou, a lead researcher on the project. “We needed to eliminate it altogether.” This realization spurred the team to explore cutting-edge protein degradation technologies.
Harnessing the Cell’s Own Machinery: PROTACs and Molecular Glues
The research team focused on two advanced therapeutic strategies: PROTACs (Proteolysis-Targeting Chimeras) and molecular glues. Both methods leverage the cell’s natural protein degradation system, the ubiquitin-proteasome pathway, to mark target proteins for destruction. However, molecular glues offer distinct advantages, including their small size, favorable pharmacokinetic profiles, and potential for oral management, making them highly attractive for drug development.
MG-HuR2: A Front-Runner in Targeted Protein Degradation
After synthesizing and rigorously testing dozens of candidate compounds,one molecular glue,MG-HuR2,emerged as a standout. ”MG-HuR2 not only met every major druglikeness criterion, it demonstrated powerful activity at ultra-low concentrations,” states Kassabri, a key contributor to the study.
In preclinical studies using breast cancer cell lines, MG-HuR2 proved remarkably effective:
HuR Reduction: It reduced HuR protein levels by up to 85%.
Oncogene Disruption: It interfered with the expression of crucial downstream oncogenes, including Bcl2 and FOXQ1. Inhibition of malignant Growth: It substantially inhibited cancer cell proliferation, survival, and the growth of 3D tumor spheroids.
The Biphasic “Hook Effect”: A Novel Mechanism of Action
A particularly striking characteristic of these HuR degraders is their unusual biphasic “hook effect.” While activity typically diminishes at intermediate doses – a known phenomenon in PROTAC technology - the researchers observed a surprising rebound in efficacy at higher concentrations. This novel behavior, previously uncharacterized, was further elucidated through computational modeling.
The modeling revealed that this effect stems from MG-HuR2’s ability to engage two distinct RNA-binding pockets on the HuR protein. “The degradation pattern was unusual,” Dr. Benhamou notes. “But rather than a flaw,it turned out to be a clue. Our degraders bind at multiple sites, giving them a broader reach and potentially more durable effects.” This discovery opens new avenues for targeting other dynamic RNA-binding proteins with similar complex structures.
Profound Implications for Cancer and Beyond
The implications of this research are far-reaching. Beyond breast cancer, HuR is implicated in a wide range of malignancies and inflammatory diseases. MG-HuR2 and its related compounds provide a promising roadmap for developing drugs against a class of proteins previously considered inaccessible to modern medicinal chemistry.
Currently,MG-HuR2 represents a significant milestone as a promising lead compound in the field of targeted protein degradation. As Dr. benhamou aptly summarizes, “We’re not just inhibiting cancer’s messages-we’re dismantling its messengers.”
Source: Hebrew University of Jerusalem
Journal Reference:* Kassabri,L. & Benhamou,R. I.,(2025). Druglike Molecular Degraders of the Oncogenic RNA-Binding Protein HuR. JACS Au*. doi.org/10.1021/jacsau.5c00551
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