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

<h2>Summary</h2> 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. This study introduces two innovative proteolysis-targeting chimeras (PROTACs), AN-1 and AN-2, designed to degrade BCL-X_L, a key anti-apoptotic protein in the BCL-2 family. Optimized from ABT-263, these PROTACs utilize MDM2 as an E3 ligase, a strategy not previously used in GBM therapy. Our approach leverages the high expression of MDM2 in GSCs and low expression in platelets, enhancing therapeutic specificity and reducing the risk of thrombocytopenia—a key side effect of BCL-X_L inhibition. Both <i>in vitro</i> and <i>in vivo</i> studies show that AN-1 and AN-2 effectively inhibit GSC proliferation, promote apoptosis, and significantly improve survival rates without inducing thrombocytopenia. This study highlights the potential of targeting underexplored E3 ligases in cancer therapy and offers a selective approach to treating GBM, overcoming current treatment limitations.