PROTACCB1R Degrader-1 is a potent and selective CB1R PROTAC degrader that employs the ubiquitin-proteasome system (UPS) to facilitate CB1R degradation, showing a DC50 of 3.37 μM in MCF-7 cells while exhibiting no effect on CB2R. It reduces CB1R-associated downstream signaling pathways (p-AKT, p-ERK, BCL2, and MCM5), thus inhibiting breast cancer cell proliferation and inducing apoptosis. PROTACCB1R Degrader-1 is applicable for breast cancer-related research.

PROTAC CB1R Degrader-1 (Pro-CB8) effectively induces significant CB1R degradation in MCF-7 cells in a dose- and time-dependent manner (DC50 = 3.37 μM) within a concentration range of 0.1-20 μM over 6-48 hours. This compound also leads to a notable reduction of CB1R levels in MDA-MB-231 cells, demonstrating broader applicability. At concentrations of 0-10 μM over 6-48 hours, it downregulates expression of cancer-related proteins (p-AKT, p-ERK) and genes (BCL2, MCM5) in breast cancer cells such as MCF-7 and MDA-MB-231. Furthermore, PROTAC CB1R Degrader-1 (0-10 μM, 48 hours) selectively decreases the viability and proliferation of these cancer cells while sparing healthy fibroblasts and induces significant apoptosis in both MCF-7 and MDA-MB-231 cell lines. In 3D experimental models, a concentration of 10 μM causes substantial and sustained disintegration of MCF-7 and MDA-MB-231 tumor spheroids, with effects observable from day 3 and persisting throughout the observation period.

PROTAC CB1R Degrader-1 (5 mg/kg, intraperitoneal injection, single administration) exhibits very low brain tissue permeability in mice, making it difficult to cross the blood-brain barrier.