Synthesis of selective BCL-XL PROTAC and potent antitumor activity in glioblastoma

Glioblastoma (GBM), the most aggressive and treatment-resistant form of brain cancer, is significantly influenced by GBM stem cells (GSCs), which contribute to tumor initiation and recurrence. In this study, we introduce two novel proteolysis-targeting chimeras (PROTACs), AN-1 and AN-2, engineered to degrade BCL-X _L , a critical anti-apoptotic protein in the BCL-2 family. These PROTACs are optimized from ABT-263 and uniquely utilize MDM2 as an E3 ligase, a strategy not previously employed in GBM therapy. Our approach leverages the high expression of MDM2 in GSCs versus its low expression in platelets, enhancing therapeutic specificity and reducing the risk of thrombocytopenia—a major side effect of direct BCL-X _L inhibition. Both in vitro and in vivo studies demonstrate that AN-1 and AN-2 effectively inhibit GSC proliferation, promote apoptosis, and substantially improve survival rates without inducing thrombocytopenia. This work not only highlights the potential of targeting underutilized E3 ligases for cancer therapy but also suggests a highly selective approach for treating GBM that might overcome the current limitations of existing therapies.