1. Identification of phenyl-pyridine-2-carboxylic acid derivatives as novel cell cycle inhibitors with increased selectivity for cancer cells.
- Author
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Berthel SJ, Marks IM, Yin X, Mischke SG, Orzechowski L, Pezzoni G, Sala F, and Vassilev LT
- Subjects
- Animals, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Carboxylic Acids therapeutic use, Cell Survival drug effects, Drug Evaluation, Preclinical, Drug Screening Assays, Antitumor, Female, Humans, Inhibitory Concentration 50, Mice, Mice, Nude, Pyridines therapeutic use, Structure-Activity Relationship, Tumor Cells, Cultured, Antineoplastic Agents pharmacology, Carboxylic Acids pharmacology, Cell Cycle drug effects, Mammary Neoplasms, Experimental drug therapy, Pyridines pharmacology
- Abstract
Ro 41-4439, a phenyl-pyridine-2-carboxylic acid derivative, was identified by a cell-based screening approach that exploits the differences between normal and cancer cells in their sensitivity to cytotoxic agents. This compound showed low micromolar antiproliferative activity and cytotoxicity against a broad panel of human cancer cell lines in vitro, and over 10-fold selectivity to cancer cells when tested in parallel with a panel of proliferating normal human cells. Cytotoxicity of Ro 41-4439 is due to arrest of cell cycle progression in mitosis followed by induction of apoptosis. Four-week treatment of nude mice bearing established mammary tumor xenografts (MDA-MB-435) with well-tolerated doses of the compound showed 73% inhibition of tumor growth. Limited exploration of structure-activity relationships involving side chain length, and aryl and pyridine rings allowed for the identification of more potent analogs.
- Published
- 2002
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