Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of S phingosine Kinase 1

Pharmaceuticals
Sonam RoyMd Imtaiyaz Hassan

Abstract

Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC50 values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation.

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Citations

Feb 11, 2021·Journal of Biomolecular Structure & Dynamics·Sonam RoyMd Imtaiyaz Hassan
Sep 19, 2021·Cancer Cell International·Ahmed OlatundeJavad Sharifi-Rad

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Methods Mentioned

BETA
isothermal titration calorimetry
fluorescence binding
column chromatography
acylation
ELISA

Software Mentioned

ChemBio3D Ultra
MicroCal Origin
Discovery Studio Visualizer
AutoDock Vina
PyMOL

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