ArticleACS medicinal chemistry letters2016
Structural Requirements and Docking Analysis of Amidine-Based Sphingosine Kinase 1 Inhibitors Containing Oxadiazoles.
Article in ACS medicinal chemistry letters, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 23 citations in OpenAlex.
- Discovery of Sphingosine Kinase Inhibition by Modified Quinoline-5,8-Diones.Pharmaceuticals (Basel, Switzerland) · 2025Article
- The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target.Cancer cell international · 2024Review
- Room Temperature Synthesis of Bioactive 1,2,4-Oxadiazoles.International journal of molecular sciences · 2023Review
- Discovery of In Vivo Active Sphingosine-1-phosphate Transporter (Spns2) Inhibitors.Journal of medicinal chemistry · 2022Article
- Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4).Pharmaceuticals (Basel, Switzerland) · 2022Article
- Exploiting activity cliffs for building pharmacophore models and comparison with other pharmacophore generation methods: sphingosine kinase 1 as case study.Journal of computer-aided molecular design · 2022Article
- Identifying novel sphingosine kinase 1 inhibitors as therapeutics against breast cancer.Journal of enzyme inhibition and medicinal chemistry · 2020Article
- In Silico Characterization of Structural Distinctions between Isoforms of Human and Mouse Sphingosine Kinases for Accelerating Drug Discovery.Journal of chemical information and modeling · 2019Article
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sphingosine 1-phosphate (S1P) is a potent growth-signaling lipid that has been implicated in cancer progression, inflammation, sickle cell disease, and fibrosis. Two sphingosine kinases (SphK1 and 2) are the source of S1P; thus, inhibitors of the SphKs have potential as targeted cancer therapies and will help to clarify the roles of S1P and the SphKs in other hyperproliferative diseases. Recently, we reported a series of amidine-based inhibitors with high selectivity for SphK1 and potency in the nanomolar range. However, these inhibitors display a short half-life. With the goal of increasing metabolic stability and maintaining efficacy, we designed an analogous series of molecules containing oxadiazole moieties. Generation of a library of molecules resulted in the identification of the most selective inhibitor of SphK1 reported to date (705-fold selectivity over SphK2), and we found that potency and selectivity vary significantly depending on the particular oxadiazole isomer employed. The best inhibitors were subjected to in silico molecular dynamics docking analysis, which revealed key insights into the binding of amidine-based inhibitors by SphK1. Herein, the design, synthesis, biological evaluation, and docking analysis of these molecules are described.
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