Innovative Molecular Degraders Offer New Hope for Aggressive Breast Cancer Treatment

Researchers from the Hebrew University of Jerusalem have made a significant breakthrough in cancer therapy by creating novel drug-like molecules that target previously 'undruggable' proteins associated with aggressive breast cancer. Led by Dr. Raphael Benhamou and supervised by M.Sc. student Liann Kassabri, the team developed molecules capable of degrading HuR (ELAVL1), an RNA-binding protein that plays a critical role in stabilizing oncogenes and promoting tumor growth.

HuR has long been considered resistant to conventional drug targeting because of its flexible structure and absence of traditional active sites. Its overexpression in many cancers, especially breast cancer, makes it a dangerous protein that enhances the survival and proliferation of malignant cells. Recognizing the limitations of simply blocking HuR, the researchers aimed to eliminate it entirely, which resulted in a marked increase in anticancer effectiveness — up to four orders of magnitude better than prior approaches.

To achieve this, the team employed advanced strategies like PROTACs and molecular glues, with a particular focus on small-sized molecular glues that offer favorable pharmacokinetics and oral availability. After screening numerous candidates, they identified MG-HuR2 as a leading compound. This molecule demonstrated potent activity at very low concentrations, reducing HuR levels in breast cancer cells significantly and disrupting the expression of downstream oncogenes such as Bcl2 and FOXQ1. The degradation of HuR led to a substantial decrease in tumor cell proliferation, survival, and spheroid growth, with findings published in the journal JACS Au.

An intriguing aspect of MG-HuR2 is its biphasic 'hook effect,' a phenomenon where drug activity diminishes at intermediate doses but rebounds at higher concentrations. Computational studies revealed that this effect arises because the molecule can engage two distinct RNA-binding pockets on HuR, offering insights into novel targeting mechanisms for dynamic RNA-binding proteins. This multi-site engagement suggests potential for more durable and effective therapeutic strategies.

Beyond breast cancer, HuR's involvement in various other malignancies and inflammatory processes broadens the significance of this research. The development of MG-HuR2 and related degraders paves the way for targeting proteins once deemed intractable, opening new vistas in precision medicine. As Dr. Benhamou emphasizes, this approach transcends mere inhibition by dismantling cancer's signaling pathways at a fundamental level.

This breakthrough signifies a major advance in the field of targeted protein degradation, promising new therapeutic options for challenging cancers and diseases driven by elusive proteins.