Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors

Heba Alshaker, Shyam Srivats, Danielle Monteil, Qi Wang, Caroline M. R. Low, Dmitri Pchejetski

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)
6 Downloads (Pure)

Abstract

Purpose: Sphingosine kinase 1 (SK1) is a protooncogenic enzyme expressed in many human tumours and is associated with chemoresistance and poor prognosis. It is a potent therapy target and its inhibition chemosensitises solid tumours. Despite recent advances in SK1 inhibitors synthesis and validation, their clinical safety and chemosensitising options are not well described. In this study, we have designed, synthesised and tested a new specific SK1 inhibitor with a low toxicity profile.

Methods: Field template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models.

Results: Field template analysis of three known SK1 inhibitors, SKI-178, 12aa and SK1-I, was performed and compound screening identified six potential new SK1 inhibitors. SK1 activity assays in both cell-free and in vitro settings showed that two compounds were effective SK1 inhibitors. Compound SK-F has potently decreased cancer cell viability in vitro and sensitised mouse breast tumours to docetaxel (DTX) in vivo, without significant whole-body toxicity.

Conclusion: Through field template screening, we have identified a new SK1 inhibitor, SK-F, which demonstrated antitumour activity in vitro and in vivo without overt toxicity when combined with DTX.
Original languageEnglish
Pages (from-to)33–43
Number of pages11
JournalBreast Cancer Research and Treatment
Volume172
Issue number1
Early online date24 Jul 2018
DOIs
Publication statusPublished - Nov 2018

Keywords

  • Sphingosine kinase 1
  • Molecular field template
  • Kinase inhibitor
  • Chemosensitisation
  • Docetaxel
  • Breast cancer
  • POTENTIAL THERAPEUTIC TARGET
  • PROSTATE-CANCER CELL
  • BREAST-CANCER
  • PROTEASOMAL DEGRADATION
  • FTY720
  • GROWTH
  • EXPRESSION
  • SPHINGOSINE-1-PHOSPHATE
  • IMMUNOMODULATOR
  • 1-PHOSPHATE

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