Ixocarpalactone A from dietary tomatillo inhibits pancreatic cancer growth by targeting PHGDH

3-Phosphoglycerate dehydrogenase (PHGDH) catalyzes the first rate-limiting step for the synthesis of glucose-derived serine by converting 3-phosphoglycerate (3-PG) to phosphohydroxypyruvate (p-Pyr), which has been reported to associate with tumorigenesis in many cancers. IoxA, a natural withanolide obtained from dietary tomatillo (Physalis ixocarpa), showed significant PHGDH inhibitory activity with IC50 value of 1.66 ± 0.28 μM, and it was further confirmed to bind directly to PHGDH by MST assay. Molecular docking demonstrated that IoxA coordinated at the allosteric site of PHGDH, which was consistent with the non-competitive kinetic. Meanwhile, IoxA selectively inhibited the proliferation of high PHGDH-expressing cancer cell lines (SW1990, MCF-7 and Hela) and showed no obvious cytotoxicities on normal human cells (LO2, L929 and HPDE6-C7). Especially, IoxA showed a dose-dependent proapoptotic activity against SW1990 cells in micromolar concentration as detected by flow cytometry and Western blot analysis. DARTS and siRNA assays further demonstrated that IoxA directly target at PHGDH to inhibit the proliferation of SW1990 cells. Furthermore, IoxA significantly inhibited the tumor growth in SW1990 xenograft mouse model with low toxicities, suggesting its potential therapeutic application in pancreatic cancer treatment. Therefore, IoxA was identified as the novel natural PHGDH inhibitor with high targeting and low toxicities for treatment of pancreatic cancers.