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Department of Medicinal Chemistry [R. D. J., C. M. I.] and Division of Molecular Pharmacology, Huntsman Cancer Institute [D. A. J.], University of Utah, Salt Lake City, Utah 84112, and Institute of Applied Sciences, The University of the South Pacific, Suva, Fiji Islands [W. A.]

¹ To whom requests for reprints should be addressed, at Department of Medicinal Chemistry, University of Utah, 30 South 2000 East, Room 307, Salt Lake City, UT 84112-9453

The binding of epidermal growth factor to its receptor activates the mitogen-activated protein kinase pathway. This pathway has been identified as a vital link between membrane-bound Ras and nuclear events and, therefore, is a potential target for chemotherapeutic drugs. We reported previously that naamidine A (NA), an alkaloid from the calcareous sponge Leucetta chagosensis, potently inhibited epidermal growth factor-stimulated DNA synthesis. In this current study, we demonstrate that in addition to its antimitogenic effects (complete inhibition of DNA synthesis at 0.78 µM in A-431 cells after 30 h), NA at 1.56 µM caused cells to arrest in the G₁ phase of the cell cycle. In vitro kinase, in-gel kinase, and Western blotting experiments demonstrate that extracellular signal-regulated kinase (ERK) 1 and ERK2 are primary molecular targets for NA in A-431 cells. Treatment with NA at concentrations between 0.78 and 3.13 µM produces changes in the phosphorylation states of the ERKs, and strongly induces the phosphotransferase activity of the ERK enzymes. Our data indicate that treatment with NA generates a robust ERK signal. NA is the first small molecule reported to cause this effect on the ERK kinases and consequent G₁ cell cycle arrest.