A Thieno[3,2-D] pyrimidine class of p110α/GDH1 dual inhibitor SBS-873 suppresses TNBC growth by inhibiting PI3K/mTOR signaling and inducing ferroptosis through glutathione depletion.

Background

Genetic alterations in phosphoinositide 3-kinase (PI3K) signaling are frequently observed in triple-negative breast cancer (TNBC), with the p110α subunit being the most mutated. Although this identifies p110α as a promising therapeutic target, selective inhibitors have demonstrated limited efficacy. Therefore, this study aimed to investigate the therapeutic potential and underlying mechanisms of SBS-873, a novel thieno[3,2-D]pyrimidine-based p110α inhibitor.

Methods

SBS-873 antitumor activity was evaluated in vitro and in TNBC xenograft models. The docking and biochemical assays confirmed the binding affinity of the compound. Protein and mRNA expression were analyzed by Western blotting and qRT-PCR, with immunofluorescence and immunohistochemistry confirming protein levels. Metabolic function was assessed using Seahorse analysis. Oxidative stress and lipid peroxidation were measured through the reduced glutathione test and malondialdehyde assay, while gene knockout validated the mechanism.

Results

SBS-873 exhibited broad antiproliferative activity across multiple cancer cell lines, with marked selectivity toward TNBC cells while sparing non-tumorigenic mammary cells. Mechanistically, SBS-873 suppressed the PI3K/AKT/mTOR signaling pathway by downregulating p110α and concurrently inhibited GDH1, a critical regulator of glutamine metabolism, redox homeostasis, and epithelial-mesenchymal transition (EMT). GDH1 inhibition resulted in glutathione depletion, GPX4 impairment, and increased lipid peroxidation, ultimately inducing ferroptotic cell death. In vivo, SBS-873 significantly reduced tumor growth in TNBC xenografts without observable toxicity, accompanied by suppression of both p110α and GDH1.

Conclusion

These findings identify SBS-873 as a first-in-class dual inhibitor targeting both p110α and GDH1, offering a promising therapeutic strategy that simultaneously disrupts proliferative signaling, metabolic adaptation, and metastatic potential in TNBC.