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

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...

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Autores principales: Alshaker, Heba, Srivats, Shyam, Monteil, Danielle, Wang, Qi, Low, Caroline M. R., Pchejetski, Dmitri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208908/
https://www.ncbi.nlm.nih.gov/pubmed/30043096
http://dx.doi.org/10.1007/s10549-018-4900-1
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author Alshaker, Heba
Srivats, Shyam
Monteil, Danielle
Wang, Qi
Low, Caroline M. R.
Pchejetski, Dmitri
author_facet Alshaker, Heba
Srivats, Shyam
Monteil, Danielle
Wang, Qi
Low, Caroline M. R.
Pchejetski, Dmitri
author_sort Alshaker, Heba
collection PubMed
description 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10549-018-4900-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-62089082018-11-09 Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors Alshaker, Heba Srivats, Shyam Monteil, Danielle Wang, Qi Low, Caroline M. R. Pchejetski, Dmitri Breast Cancer Res Treat Preclinical Study 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s10549-018-4900-1) contains supplementary material, which is available to authorized users. Springer US 2018-07-24 2018 /pmc/articles/PMC6208908/ /pubmed/30043096 http://dx.doi.org/10.1007/s10549-018-4900-1 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
spellingShingle Preclinical Study
Alshaker, Heba
Srivats, Shyam
Monteil, Danielle
Wang, Qi
Low, Caroline M. R.
Pchejetski, Dmitri
Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors
title Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors
title_full Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors
title_fullStr Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors
title_full_unstemmed Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors
title_short Field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors
title_sort field template-based design and biological evaluation of new sphingosine kinase 1 inhibitors
topic Preclinical Study
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208908/
https://www.ncbi.nlm.nih.gov/pubmed/30043096
http://dx.doi.org/10.1007/s10549-018-4900-1
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