GZD-257

Glioblastoma (GBM) is a primary malignant brain tumor that seriously threatens human health. Focal adhesion kinase (FAK) is an important target for GBM drug research and regulates tumor cell proliferation, invasion, and drug resistance. Although a large number of FAK inhibitors have entered clinical research, there are few reports on the treatment of GBM with FAK inhibitors. Herein, TAE-226, the earliest FAK inhibitor to enter clinical trials, was used as the lead compound, and a macrocyclization-based structural optimization strategy was adopted to develop novel FAK inhibitors. The optimized macrocyclic compound GZD-257 exhibited excellent in vitro anti-GBM activity. The IC₅₀ values of GZD-257 against FAK, glioblastoma cells U118-MG, and U87-MG reached 14.30 nM, 1.64 μM, and 1.40 μM, respectively. Interestingly, the IC₅₀ value of GZD-257 against Pyk2 was 68.20 nM, which performed 4.77-fold selectivity with FAK. In addition, GZD-257 showed excellent blood-brain barrier (BBB) penetration, with a Pe value of 43.85, significantly higher than that of the positive control TAE-226 (24.18). Finally, flow cytometry studies indicated that GZD-257 could significantly induce apoptosis of U118-MG cells and arrest the cell cycle at the G2/M phase. Molecular docking studies suggested that GZD-257 was a highly promising ATP-competitive FAK inhibitor.