FTY720 is a novel immunomodulator that has been approved by FDA for the treatment of relapsing Multiple sclerosis (MS). It features a unique mechanism of action by reducing circulating levels of naïve lymphocytes by increasing their localization and sequestration in secondary lymphoid organs. It binds several S1P receptors and subsequently induces their internalization and intracellular partial degradation. This blocks the signal that is necessary for egress of lymphocytes from thymus and peripheral lymphoid organs and therefore induces lymphopenia. Recently, FTY720 was found to exhibit anticancer activities in various types of cancers through different signaling pathways independent of S1P1 signaling. For example, our laboratory found that FTY720 induced apoptosis in HCC cells through ROS-PKCδ-caspase-3 signaling axis. Taken together, this prompted us to initiate modifications on FTY720 to develop more potent anticancer agents devoid of immunosuppressive activity.
OSU-2S, one of the FTY720 derivatives shows most potent cell viability suppression activity in four HCC cell lines. It was derived from FTY720 by replacing the pro-(S)-hydoxymethyl of FTY720 with a propyl group, therefore abrogating the immunosuppressive activity. On the other hand, the anticancer activity was increased by one fold compared to FTY720. Mechanistically, OSU-2S induced hepatocellular carcinoma cells to undergo caspase-3 dependent apoptosis in the same manner as that of FTY720 but at lower concentration.
OSU-DY-7 is another derivative that shows high potency in lymphocytic leukemia and primacy B cells purified from chronic lymphocytic leukemia patients. Molecular mechanism studies demonstrate that OSU-DY-7 down regulated the expression level of BIRC5 through transcriptional mechanism by activating MAPK p38. BIRC5 is a cell survival factor and its down regulation may contribute to the cell death.
Over all, two anticancer agents, OSU-2S and OSU-DY-7 were developed from FTY720 and they showed strong anticancer activity in HCC cells and lymphocytic leukemia cells respectively through distinct mechanisms of action.
PAK1 is a serine/threonine kinase that was the first PAK member identified to be downstream effectors of small GTPase Cdc42 and Rac and regulates cell motility and cytoskeleton. PAK1 was also found to be implicated in a wide range of cellular process, such as cell proliferation and apoptosis rendering it an attractive therapeutic target. In this study, we report on the development of a potent and/or selective PAK1 inhibitors based on a novel PDK1 inhibitor OSU-03012, which also inhibits PAK1 directly. The results show that compound YM-4 and YM-15 demonstrate stronger PAK1 inhibitory activity in a ATP-competitive manner, and more importantly, are much less effective in inhibiting PDK1 kinase activity, even though they are not specific PAK1inhibitor.