Identification of phenyl-pyridine-2-carboxylic acid derivatives as novel cell cycle inhibitors with increased selectivity for cancer cells.
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.
Berthel
Steven J
SJ
Discovery Chemistry, Roche Research Center, Hoffmann-La Roche Inc, Nutley, NJ 07110, USA.
Marks
Ian M
IM
Yin
Xuefeng
X
Mischke
Steven G
SG
Orzechowski
Lucja
L
Pezzoni
Gabriella
G
Sala
Franca
F
Vassilev
Lyubomir T
LT
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002264:Carboxylic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D011725:Pyridines; C469293:Ro 41-4439