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Review Article

Inhibitors of <i>Ras</i>-Transformation

[ Vol. 3 , Issue. 3 ]

Author(s):

Kenji Sugita* and Mitsuaki Ohtani   Pages 323 - 334 ( 12 )

Abstract:


Ras-oncogene is now thought to be one of the most important oncogenes which is evidenced in the correlation with human cancers. Point mutation in ras-gene correlates with transformation caused by ras and is found in human cancers with high frequency, such as 90% in pancreatic cancer, 50% in colon cancer and 30% in lung cancer. Ras (product of ms-oncogene) has GTPase activity and loses its activity with point mutation, leading to transformation. Active GTP-binding form of Ras is a key molecule of signal transduction in cell growth, differentiation and transformation.

Inhibitors of ms-transformation will be good candidates of anti-cancer agents. Although many inhibitors of rasĀ­ transformation have been reported up to now including macromolecules (genes, nucleotides, antibodies), we summarize the small-molecule compounds, which inhibit ms-transformation in direct or indirect manner in this review. Direct inhibitors of ras include inhibitors of farnesylation of Ras. Farnesyltransferase inhibitors (L- 744,832, etc) include peptidomimetics with the rational drug design for C-terminus of Ras and natural products. Inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase (Lovastatin, etc) which block cholesterol metabolism, inhibit farnesylation of Ras by decreasing the amount of the substrate of farnesyltransferase (Frase). Indirect inhibitors of ras with known mechanisms include the inhibitor of inositol monophosphate (IMP) dehydrogenase (oxanosine), the inhibitor of mitogen-activated protein kinase kinase (MAPK kinase)(PD98059), the inhibitor of MAPK (apigenin), the inhibitors of protein kinase C (PKC) (UCN- 01, etc), the inhibitors of phosphatidylinositol 3-kinase (Pl3K) (Wortmannin and L-294002), the inducer of the transcription factor JunD (oxamflatin) and the inhibitors of histone deacetylase [trichostatin A (TSA) and trapoxins]. Almost all compounds are now under development, and will be evaluated in clinical studies as anticancer agents.

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