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

• Main Authors: Sonam Roy, Amarjyoti Das Mahapatra, Taj Mohammad, Preeti Gupta, Mohamed F. Alajmi, Afzal Hussain, Md. Tabish Rehman, Bhaskar Datta, Md. Imtaiyaz Hassan
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Pharmaceuticals
• Subjects: sphingosine kinase-1; sphingosine-1-phosphate; cancer therapy; enzyme inhibition; kinase inhibitors; molecular docking
• Online Access: https://www.mdpi.com/1424-8247/13/6/118

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.