Novel oxadiazole analogs as anticancer agents: Design, synthesis, in vitro and in vivo biological evaluation, and computer studies of sphingosine kinase inhibitors.

Sphingosine kinases (SphKs) have emerged as novel therapeutic targets for treating cancer and inflammation via the SphK/S1P signaling pathway. However, the development of selective SphK inhibitors has been challenging because of their limited specificity. In this study, we used pharmacophore- and docking-based virtual screening to identify the lead compound DTD-8 (SphK1 IC₅₀ = 79 ± 0.73 μM) and then optimized the structure through structure-based drug design. Our newly synthesized 1,2,4-oxadiazole derivative, compound 22c, demonstrated selective inhibition against SphK2 (IC₅₀ = 2.24 ± 0.60 μM) over SphK1 (IC₅₀ = 64.20 ± 1.53 μM), representing 28-fold selectivity for SphK2. It also exhibited more potent anticancer activity against DU145 cells (IC₅₀ = 3.09 ± 0.67 μM) than cisplatin (IC₅₀ = 10.67 ± 1.00 μM) owing to its ability to induce S/G2 phase arrest and apoptosis. In rats, Compound 22c showed favorable pharmacokinetic properties, including good metabolic stability (T₁/₂ = 19.6 h) and high plasma exposure (AUC₀-t = 1077.40 ng h/mL), along with promising in vivo tumor growth inhibition (TGI = 65.96 %). Given its moderate oral bioavailability (F = 54.88 %) and potent anticancer effects, 22c requires further investigation. These findings provide valuable insights for developing novel SphK2-targeted anticancer agents.