Glycans Meet Sphingolipids: Rational Structure-Based Design of a New Generation of Sphingosine Kinase Inhibitors

Sphingosine kinases, SK1 and SK2, are enzymes localized respectively in the cytosol and in intracellular compartments, which catalyze the production of sphingosine-1-phosphate (S1P) in an ATP-dependent manner. Solid experimental evidences implicate the S1P axis in different pathological conditions (e.g. cancer, inflammatory disease, fibrosis), and aberrant S1P levels and/or SKs expression have been associated with diseases progression [1]. In this regards, the manipulation of S1P axis using chemical tools has been exploited either looking at the inhibition of SK activity and by the modulation of S1P receptors signaling. Specifically, a wide number of SK1 inhibitors have been developed to date. However, most of them are still limited by low potency and/or specificity among SK subtypes, indicating the need for new and more efficient SK1 inhibitors. In this framework, we report here on an original approach for the rational structure-based design of SK1 inhibitors. It relies on the integration of the information coming from the SK1-co-crystal structure of known validated inhibitors into pharmacophoric models. This approach aims at the development of better ‘molecular fitting’ inhibitors by using glycans as an anchoring polar head allowing to hold inhibitors at the J-shaped hydrophobic binding pocket of SK [2]. In particular, in this communication we report on the rational structure-based design and stereoselective synthesis of glycan-containing PF543 analogues (Figure 1), one of the most potent SK1 inhibitors reported so far. Moreover, a preliminary evaluation of the role of the new synthesized SK inhibitors in TGFβ-induced fibrosis of murine myoblasts to confirm the rationale of the proposed approach is described.