SCH 51344, an inhibitor of RAS/RAC-mediated cell morphology pathway.
RAS interacts with multiple targets in the cell and controls at least two signaling pathways, one regulating extracellular signal-regulated kinase (ERK) activation and the other controlling membrane ruffling formation. These two pathways appear to act synergistically to cause transformation. Human smooth muscle alpha-actin promoter is repressed in RAS-transformed cells and derepressed in revertant cell lines, suggesting that it is a sensitive marker to follow phenotypic changes in fibroblast cells. SCH 51344 is a pyrazoloquinoline derivative identified on the basis of its ability to derepress alpha-actin promoter in RAS-transformed cells. Previous studies have shown that SCH 51344 is a potent inhibitor of RAS transformation. However, SCH 51344 had very little effect on the activities of proteins in the ERK pathway, suggesting that it inhibits RAS transformation by a novel mechanism. Recently, we have demonstrated that SCH 51344 specifically blocks membrane ruffling induced by activated forms of H-RAS, K-RAS, N-RAS, and RAC. Treatment of fibroblast cells with this compound had very little effect on RAS-mediated activation of ERK and JUN kinase activities. SCH 51344 was effective in inhibiting the anchorage-independent growth of Rat-2 fibroblast cells transformed by the three forms of oncogenic RAS and RAC V12. These results indicate that SCH 51344 inhibits a critical component of the membrane ruffling pathway downstream from RAC and suggest that targeting this pathway may be an effective approach to inhibiting transformation by RAS and other oncogenes.
Kumar
C C
CC
Department of Tumor Biology, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA. Chandra.kumar@spcorp.com
Ohashi
K
K
Nagata
K
K
Walsh
A
A
Bar-Sagi
D
D
Mizuno
K
K
D000199:Actins / Q000235:genetics; D000634:Aminoquinolines / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D004789:Enzyme Activation; D017930:Genes, Reporter; D006801:Humans; D011401:Promoter Regions, Genetic; D011494:Protein Kinases / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D020744:rac GTP-Binding Proteins / Q000037:antagonists & inhibitors*; D018631:ras Proteins / Q000037:antagonists & inhibitors*
D000199:Actins; D000634:Aminoquinolines; D016588:Anticarcinogenic Agents; D011720:Pyrazoles; C096472:SCH 51344; D011494:Protein Kinases; D020744:rac GTP-Binding Proteins; D018631:ras Proteins