Phenylethynyl-substituted Heterocycles Inhibit Cyclin D1 and Induce the Expression of Cyclin-dependent Kinase Inhibitor p21 in Colorectal Cancer Cells.

Fluorinated, phenylethynyl-substituted heterocycles that possessed either an -methylamino or -dimethylamino group attached to heterocycles including pyridines, indoles, 1-indazoles, quinolines, and isoquinolines inhibited the proliferation of LS174T colon cancer cells in which the inhibition of cyclin D1 and induction of the cyclin-dependent kinase inhibitor-1 (., p21) served as a readout for antineoplastic activity at a cellular level. On a molecular level, these agents, particularly 4-((2,6-difluorophenyl)ethynyl)--methylisoquinolin-1-amine and 4-((2,6-difluorophenyl)ethynyl)-,-dimethylisoquinolin-1-amine, bound and inhibited the catalytic subunit of methionine S-adenosyltransferase-2 (MAT2A).