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

Abstract

PurposeSphingosine 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.MethodsField template molecular modelling was used for compound design. Lead compounds were tested in cell and mouse cancer models.ResultsField 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.ConclusionThrough 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 materialThe online version of this article (10.1007/s10549-018-4900-1) contains supplementary material, which is available to authorized users.

Transcriptome-Wide Effects of Sphingosine Kinases Knockdown in Metastatic Prostate and Breast Cancer Cells: Implications for Therapeutic Targeting

“…These inhibitors are often proposed to be used as “sensitisers” to chemo- and radiotherapy and can be used as free drugs or in nanoparticle settings (Alshaker et al, 2017; Wang et al, 2017; Yee et al, 2017). Their specificity has significantly increased with the recent discovery of SK1 structure (Wang et al, 2013) and the use of computer modeling methods (Alshaker et al, 2018).…”

“…Multiple SK1 and SK2 inhibitors have been synthesized and assayed in different biological systems. Selective SK1 inhibitors such as SK1-I or SK-F have been demonstrated to efficiently induce apoptosis in cancer cells (Paugh et al, 2008; Alshaker et al, 2018). A sphingosine analog FTY720 was shown to inhibit SK1 and induce cancer cell apoptosis (Wang et al, 1999; Permpongkosol et al, 2002), chemo- and radiosensitization (Pchejetski et al, 2010; Alshaker et al, 2017; Wang et al, 2017).…”

Sphingosine Kinase 1 in Breast Cancer—A New Molecular Marker and a Therapy Target

“…Similarly, we found that our selective SK1 inhibitor compound SK-F (developed using field-template modeling) alone did not alter the in vivo growth of 4T1 (mouse triple-negative breast cancer cell line) cells. However, compound SK-F sensitized mouse breast tumors to subtherapeutic doses of docetaxel (134). Contrary to docetaxel, SK-F did not induce significant mouse body or organ weight loss and did not have any additive toxicity (134).…”

“…However, compound SK-F sensitized mouse breast tumors to subtherapeutic doses of docetaxel (134). Contrary to docetaxel, SK-F did not induce significant mouse body or organ weight loss and did not have any additive toxicity (134). The immunosuppressant FTY720 is a structural analog of sphingosine and is phosphorylated to form FTY720-phosphate by SK2 [reviewed in White et al (141)].…”

The Tumorigenic Effect of Sphingosine Kinase 1 and Its Potential Therapeutic Target

“…196 In a model of human ALL xenografts in mice, FTY720 remarkably reduces the incidence of leukemia, which may be a potential treatment for Ph þ ALL but not Ph -B-ALL. 197 L-threo-dihydrosphingosine (Safingol, also DHS) showed potent SPHK-inhibiting properties 198 and was a promising anti-cancer agent, but it lacks specificity, with SPHK1, SPHK2, and PKC as targets. 199 More novel and potent inhibitors of SPHK1 are in the pipeline ( Figure 5).…”