Synthesis and biological investigation of protein phosphatase 2A‐activating compounds with dimeric tail as non‐small cell lung cancer cell death agents

Abstract

AbstractFTY720 exerts an anticancer effect through the activation of protein phosphatase 2A (PP2A), which acts as a tumor suppressor, and inhibits SK1 activity. However, FTY720 taken into the body is phosphorylated by endogenous SK2. The structure of FTY720 is well‐studied as a basis for developing SK inhibitors and PP2A activators. We synthesized analogs of PF‐543 with a dimeric tail structure and reported the efficacy of SK1 inhibition. The compounds with this structure had improved anticancer activity and stability compared with PF‐543. To confirm whether the dimeric tail structure could be applied as a PP2A‐active material, we synthesized four types of compounds with a dimeric tail structure and confirmed the anticancer activity and PP2A activation in A549 non‐small cell lung cancer cells. Compounds 2 and 4 were more cytotoxic to A549 cells than RB005, and induced similar levels of cytotoxic and PP2A activation as FTY720.