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Phenylethynyl-substituted Heterocycles Inhibit Cyclin D1 and Induce the Expression of Cyclin-dependent Kinase Inhibitor p21 Wif1/Cip1 in Colorectal Cancer Cells.

Fluorinated, phenylethynyl-substituted heterocycles that possessed either an N -methylamino or N,N -dimethylamino group attached to heterocycles including pyridines, indoles, 1 H -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 ( i.e ., p21Wif1/Cip1 ) served as a readout for antineoplastic activity at a cellular level. On a molecular level, these agents, particularly 4-((2,6-difluorophenyl)ethynyl)- N -methylisoquinolin-1-amine and 4-((2,6-difluorophenyl)ethynyl)- N , N -dimethylisoquinolin-1-amine, bound and inhibited the catalytic subunit of methionine S-adenosyltransferase-2 (MAT2A).

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