M468-4456

Serine/threonine kinase UNC-51-like kinase 1 (ULK1) is a key autophagy initiator. It regulates the process of autophagy through multiple signaling pathways and modulates the distribution and utilization of cellular resources, thus helping cells to maintain homeostasis in a constantly changing and complex physiological environment, thus targeting ULK1 to inhibit cellular autophagy would be an effective means of treating cancer. We used an integrated ligand-based and structure-based drug design approach to map the ULK1 pharmacophore model and used it for virtual screening. By establishing two-tier molecular dynamics analysis-based filter, a novel ULK1 inhibitor M468-4456 (U9) was obtained. In vitro validation showed that U9 potently inhibited ULK1 (IC₅₀ = 305 nM). Further studies revealed that U9 significantly reduced the autophagy level and proliferation ability of A549 lung cancer cells, and also promoted apoptosis. Notably, U9 showed stronger antiproliferative effects under nutrient starvation conditions, disrupting autophagy-dependent survival pathways. Taken together, these results suggest that compound U9 can be utilized as a novel ULK1 inhibitor, providing a structural framework for developing additional small-molecule therapeutics against lung cancer.