Novel Sphingosine Kinase 1 Inhibitor Suppresses Growth of Solid Tumor and Inhibits the Lung Metastasis of Triple-Negative Breast Cancer.

Abstract

Targeting sphingosine kinase 1 (SphK1) has become a novel strategy for the treatment of inflammatory bowel disease and cancer via 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 28 selectively inhibits SphK1 and exhibits higher anti-proliferative activity compared to the positive compound PF-543 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 28 can suppress in vivo 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 PF-543. Collectively, compound 28 represents a promising lead compound for the treatment of solid tumor and the metastasis.

• Authors: Shurui Zhang, Xiaoxu Chen, Chenglin Wu, Hui Xu, Xiong Xie, Mingshun Feng, Shulei Hu, Hudagula Bai, Feng Gao, Linjiang Tong, Jian Ding, Hong Liu, Zuoquan Xie, Jiang Wang
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 65 Issue 11 Pg. 7697-7716 (06 09 2022) ISSN: 1520-4804 [Electronic] United States
• PMID: 35439002 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Lysophospholipids
• Phosphotransferases (Alcohol Group Acceptor)
• sphingosine kinase
• Sphingosine

Topics

• Humans
• Lung Neoplasms (drug therapy)
• Lysophospholipids (metabolism)
• Phosphotransferases (Alcohol Group Acceptor)
• Sphingosine (metabolism)
• Triple Negative Breast Neoplasms (pathology)