Development of PROTAC-Based Strategies for Cannabinoid Receptor Type 1 (CB₁R) Degradation in Cancer

The cannabinoid receptor type 1 (CB₁R), a key component of the endocannabinoid system (ECS), has been implicated in various oncogenic processes. Its overexpression in breast cancer has been associated with tumor progression and metastasis, primarily through regulation of the cell cycle. Given its role in cancer biology, CB₁R represents a promising therapeutic target. In this study, we utilized Proteolysis Targeting Chimera (PROTAC) technology to design and synthesize a series of bifunctional small molecules capable of selectively degrading CB₁R in cancer cells. These compounds were specifically engineered to avoid central nervous system (CNS) penetration, thereby minimizing adverse effects linked to the parent compound, Rimonabant. Several of the synthesized molecules effectively induced CB₁R degradation. The most promising lead compound not only reduced CB₁R-associated downstream signaling but also suppressed cancer cell proliferation and promoted apoptosis, highlighting its therapeutic potential. Importantly, in a 3D spheroid cancer model, the lead compound significantly reduced tumor growth compared to the known CB₁R antagonist Rimonabant, demonstrating superior efficacy in targeting both individual cancer cells and complex tumor architecture. Consistent with its design, <i>in vivo</i> evaluation confirmed that the compound does not significantly penetrate the blood-brain barrier, supporting its peripheral selectivity. Overall, our findings establish targeted CB₁R degradation via PROTACs as a viable and innovative strategy for cancer therapy, paving the way for the development of next-generation, precision-targeted therapeutics.