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Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2018

Open Access 01-11-2018 | Preclinical study

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

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

Published in: Breast Cancer Research and Treatment | Issue 1/2018

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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.
Appendix
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Metadata
Title
Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors
Authors
Heba Alshaker
Shyam Srivats
Danielle Monteil
Qi Wang
Caroline M. R. Low
Dmitri Pchejetski
Publication date
01-11-2018
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-018-4900-1

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