Lung cancer is the world's top ranked cancer, with non-small cell lung cancer accounting for over 80% of lung cancer, so it is an urgent need to find new treatment strategies for non-small cell lung cancer. Celastrol is one of the effective active ingredients in the plant Tripterygium wilfordii Hook. f., and research has found that celastrol has an inhibitory effect on non-small cell lung cancer. However, the significant toxic side effect of celastrol limits its clinical application. In this study, 9 novel celastrol derivatives were developed using PROTAC technology. Cell viability testing displayed that some compounds exhibited higher antiproliferative activity in cancer cells, and had lower toxicity to normal cells. Among them, compound MX-108 (11c) showed a high inhibitory activity with an IC