Synthesis and anti-migrative evaluation of moverastin derivatives.

Cell migration of tumor cells is essential for invasion of the extracellular matrix and for cell dissemination. Inhibition of the cell migration involved in the invasion process represents a potential therapeutic approach to the treatment of tumor metastasis; therefore, a novel series of derivatives of moverastins (moverastins A and B), an inhibitor of tumor cell migration, was designed and chemically synthesized. Among these moverastin derivatives, several compounds showed stronger cell migration inhibitory activity than parental moverastins, and UTKO1 was found to have the most potent inhibitory activity against the migration of human esophageal tumor EC17 cells in a chemotaxis cell chamber assay. Interestingly, although moverastins are considered to inhibit tumor cell migration by inhibiting farnesyltransferase (FTase), UTKO1 did not inhibit FTase, indicating that UTKO1 inhibited tumor cell migration by a mechanism other than the inhibition of FTase.

Discovery of a Highly Potent and Selective MEK Inhibitor: GSK1120212 (JTP-74057 DMSO Solvate).

Inhibition of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) represents a promising strategy for the discovery of a new generation of anticancer chemotherapeutics. Our synthetic efforts, beginning from the lead compound 2, were directed at improving antiproliferative activity against cancer cells as well as various drug properties. These efforts led to the discovery of N-{3-[3-cyclopropyl-5-(2-fluoro-4-iodophenylamino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro-2H-pyrido[4,3-d]pyrimidin-1-yl]phenyl}acetamide dimethylsulfoxide solvate (GSK1120212, JTP-74057 DMSO solvate; 1), a selective and highly potent MEK inhibitor with improved drug properties. We further confirmed that the antiproliferative activity correlates with cellular MEK inhibition and observed significant antitumor activity with daily oral dosing of 1 in a tumor xenograft model. These qualities led to the selection of 1 for clinical development.

Chemistry and biology of moverastins, inhibitors of cancer cell migration, produced by Aspergillus.

Cancer cell migration is a required step in cancer metastasis. We screened for inhibitors of cancer cell migration of microbial origin, and obtained moverastin, a member of the cylindrol family, from Aspergillus sp. F7720. However, the results of an NMR spectroscopic analysis raised the possibility that moverastin is a mixture of two diastereomers. Separation of the C-10 epimers of synthetic moverastin and a bioassay revealed that both diastereomers (moverastins A and B) had inhibitory effects on cell migration. Furthermore, we demonstrated that moverastins A and B inhibited FTase in vitro, and they also inhibited both the membrane localization of H-Ras and the activation of the PI3K/Akt pathway in EC17 cells. Thus, moverastins inhibited the migration of tumor cells by inhibiting the farnesylation of H-Ras, and subsequent H-Ras-dependent activation of the PI3K/Akt pathway.

Inhibition of neointimal proliferation in balloon-injured arteries using non-anticoagulant heparin-carrying polystyrene.

Non-anticoagulant heparin-carrying polystyrene (NAC-HCPS) has a higher activity to inhibit proliferation and migration of smooth muscle cells (SMCs) than heparin (Hep), periodate-oxidized (IO4-) Hep, and periodate-oxidized alkaline-degraded low molecular weight (IO4-LMW-) Hep. Less than 10 microg/ml of NAC-HCPS significantly inhibited the proliferation and migration of SMCs in vitro, while over 10-fold higher concentrations of Hep, IO4-Hep, and IO4-LMW-Hep were required to obtain the same inhibition. On the other hand, neointimal growth (intimal cross-section area and intimal cross-section area/medial cross-section area ratio) in vivo following vascular injury 28 days after balloon denudation in a rat carotid artery was substantially inhibited with high dose of intravenous administration (total 30 mg) of respectively IO4-Hep, IO4-LMW-Hep, and NAC-HCPS. A low-dose (total 10 mg) administration of IO4-Hep and IO4-LMW-Hep did not prevent the neointimal growth when compared with the control; only NAC-HCPS (total 10 mg) was able to significantly inhibit the neointimal. Thus, NAC-HCPS has a more-than 10-fold larger activity to inhibit SMC activities such as proliferation and migration in vitro, when comparing with Hep, IO4-Hep, and IO4-LMW-Hep; NAC-HCPS also prevents neointimal growth in vivo at lower doses.