LY103, a pomalidomide derivative, alleviates taxol resistance in NSCLC via energy metabolism crosstalk and tumor microenvironment intervention

In this study, we identified HIF 1α as a potential target for reversing taxol resistance in lung cancer by combining bioinformatics analysis with pharmacological analysis. Furthermore, pomalidomide derivative LY103 was also be synthesized by introducing an isatin analogue into the amino terminal of pomalidomide, and it has a broad antitumor spectrum and showed excellent activity against A549/Taxol cells (IC50 = 6.33 ± 0.51 μM). The results of molecular docking showed that not only LY103 was inclined to bind to HIF 1α stably, it could also form multiple hydrogen bonds with VAL376, ASP256, ILE454, and GLU455 of HIF 1α even was reduced to LY103-NH2 by nitroreductase, which was further stabilized the complex formed by them, thereby inhibiting the activity of HIF 1α. LY103 was able to significantly induce DNA damage and inhibit angiogenesis. Concurrently, LY103 activated the immune response, reduced the expression of cytokines TNF-α, IL-6, and IL-1β, thus might be inhibit the proliferation and metastasis of tumor cells. Pharmacological analysis proved that LY103 led to cell apoptosis through the mitochondrial pathway, and its combination with taxol significantly promoted this process. In general, the consumption of glutathione, the crosstalk of energy metabolism, and the improvement of the tumor microenvironment caused by LY103 eventually led to the decrease of ABCC1 protein expression and the drug resistance was reversed. The rational design of LY103 provided a basis for the application of nitro compounds in the treatment of hypoxic tumors and the reversal of taxol resistance.