SphK Inhibitor ZFP-B34 Suppresses the Growth of TNBC Cells

Sphingosine kinase 1/2 (SphK1/2) promote the initiation and advancement of breast cancers. We performed screening on a compound library of SphK inhibitors using computer molecular docking and selected the most representative compound, ZFP-B34, for testing its antitumor activity in triple-negative breast cancer (TNBC). In TNBC cell lines ZFP-B34 effectively inhibits SphK1/2 activity, induces ceramide accumulation, and results in Sphingosine 1 phosphate (S1P) depletion without altering SphK1/2 expression in TNBC cells, making it a promising novel dual inhibitor of SphK1/2. ZFP-B34 effectively inhibits cell proliferation, cell cycle progression, and migration, leading to cellular growth arrest. ZFP-B34 induces reactive oxygen species (ROS) production and mitochondrial depolarization, leading to mitochondrial dysfunction. Simultaneously, it damages DNA, ultimately resulting in apoptosis. ZFP-B34 can also inhibit the activation of Akt-mammalian target of rapamycin (mTOR) while inducing c-Jun N-terminal kinase (JNK) activation in TNBC cells. In vivo, daily intraperitoneal injection of a single dose of ZFP-B34 effectively inhibits the growth of 4T1 allografts in mice. In conclusion, ZFP-B34 is capable of inhibiting SphK1/2 and delaying the growth of TNBC cells both in vitro and in vivo.