Novel Sphingosine Kinase 1 Inhibitor Suppresses Growth of Solid Tumor and Inhibits the Lung Metastasis of Triple-Negative Breast Cancer.
Zhang S, Chen X, Wu C, Xu H, Xie X, Feng M, Hu S, Bai H, Gao F, Tong L, Ding J, Liu H, Xie Z, Wang J.
Targeting sphingosine kinase 1 (SphK1) has become a novel strategy for the treatment of inflammatory bowel disease and cancer <i>via</i> the SphK1/S1P signaling pathway. However, exploration of SphK1 inhibitor therapeutic applications has been hampered by the poor pharmacokinetic properties of these SphK1 inhibitors. Herein, we report the structural optimization and structure-activity relationship studies of a series of novel SphK1 inhibitors. The novel compound <b>28</b> selectively inhibits SphK1 and exhibits higher anti-proliferative activity compared to the positive compound <b>PF-543</b> in various cancer cells, which is associated with the induction of G0/G1 phase arrest and apoptosis; besides, it could also inhibit the cell migration. Further, compound <b>28</b> can suppress <i>in vivo</i> growth of both colon tumor and triple-negative breast tumor and inhibits the lung metastasis of triple-negative breast cancer with higher potency compared with that of <b>PF-543</b>. Collectively, compound <b>28</b> represents a promising lead compound for the treatment of solid tumor and the metastasis.