title: The antiproliferative agent MLN944 preferentially inhibits transcription.
abstract: MLN944 is a novel compound currently being codeveloped by Millennium Pharmaceuticals and Xenova Ltd. as a cancer therapeutic and is in a phase I clinical trial for solid tumors. Although MLN944 was originally proposed to function as a topoisomerase I and II inhibitor, more recent data has shown that it is a DNA-intercalating agent that does not inhibit the catalytic activity of topoisomerase I or II. We show here that MLN944 inhibits incorporation of radiolabeled precursors into RNA preferentially over incorporation into DNA and protein in HCT116 and H460 cells. To determine if MLN944 inhibits transcription, a human RNA polymerase II in vitro transcription system was used. MLN944 inhibited initiation when added before or after the formation of preinitiation complexes and inhibited elongation at higher concentrations. The preferential inhibition of initiation differentiates MLN944 from actinomycin D, which more strongly inhibits elongation. Transcription of all RNA polymerases was inhibited in nuclei isolated from HeLa cells treated with low concentrations of MLN944. Our data are consistent with transcription as the target of the potent cytotoxic effects of MLN944.
authors.affiliation: Department of Biochemistry, University of Iowa, 3130 MERF, Iowa City, IA 52242, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Byers
authors.forename: Blanca
authors.initials: B
authors.lastname: Schafer
authors.forename: Darshan S
authors.initials: DS
authors.lastname: Sappal
authors.forename: Jeffery
authors.initials: J
authors.lastname: Brown
authors.forename: David H
authors.initials: DH
authors.lastname: Price
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003609:Dactinomycin / Q000494:pharmacology; D006131:Growth Inhibitors / Q000494:pharmacology; D006801:Humans; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology*; D010619:Phenazines / Q000494:pharmacology*; D012319:RNA Polymerase II / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; C505210:MLN 944; D019384:Nucleic Acid Synthesis Inhibitors; D010619:Phenazines; D003609:Dactinomycin; D012319:RNA Polymerase II