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.
Shurui Zhang  1  2 ,  Xiaoxu Chen  2  3  4 ,  Chenglin Wu  2 ,  Hui Xu  2  4 ,  Xiong Xie  2  4 ,  Mingshun Feng  2  3  4 ,  Shulei Hu  1  2 ,  Hudagula Bai  2  4 ,  Feng Gao  2  4 ,  Linjiang Tong  2  4 ,  Jian Ding  2  3  4 ,  Hong Liu  1  2  3  4  5 ,  Zuoquan Xie  2  4 ,  Jiang Wang  2  4  5  6
Affiliations
  • 1. China Pharmaceutical University, 639 Longmian Avenue, Jiangning District, Nanjing 211198, China.
  • 2. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
  • 3. School of Life Science and Technology, ShanghaiTech University, Shanghai 200031, China.
  • 4. University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
  • 5. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 6. Lingang Laboratory, Shanghai 200031, China.
PMID: 35439002 DOI: 10.1021/acs.jmedchem.2c00040
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.

Products