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

J Med Chem. 2022 Jun 9;65(11):7697-7716. doi: 10.1021/acs.jmedchem.2c00040. Epub 2022 Apr 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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