[Inhibition of RAS-transformation by SCH51344].

ABSTRACT

RAS controls at least two signaling pathways, one regulating extracellular signal-regulated kinase (ERK) activation and the other controlling membrane ruffling formation. Activating RAS mutations are commonly found in human tumors, making RAS and its downstream signaling pathways important targets for tumor therapeutics. We have developed a reporter-gene based assay system, utilizing transformation sensitive alpha-actin promoter, to identify compounds that inhibit the transforming activity of RAS either directly or indirectly. SCH51344 is a pyrazolo-quinoline derivative, identified based on its ability to depreprses alpha-actin promoter in RAS-transformed cells and shown to be a potent inhibitor of RAS-transformation. However, this compound had very little effect on the activities of the proteins in the ERK pathway, suggesting that it inhibits RAS-transformation by a novel mechanism and acts on a signaling pathway distinct from ERK pathway. Recently, in collaboration with Dr. Dafna Bar-Sagi's group, we have shown that SCH51344 inhibits 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. Our results indicate that SCH51344 inhibits a critical component of the membrane ruffling pathway downstream from RAC and suggest that targeting the membrane ruffling pathway may be an effective approach to inhibit transformation by RAS.