Ras Inhibition

The RAS pathway offers many possibilities for the small molecule approach, including the targeting of RAS itself, modifiers of RAS activity, upstream activators, or downstream effectors. Of these approaches to inhibition of RAS activity, targeting of RAS itself has been the least successful. The development of drugs that block GTP binding and do not result in the activation of RAS has been difficult. Because of the high concentrations of GTP in a cell, it is likely that such a drug would have to be used at very high concentrations.24 Instead, most attempts to target RAS pathways have focused on RAS modifiers, downstream effectors, and upstream activators.

The modification of RAS by farnesyltransferase is essential for the proper membrane localization and activation of RAS. Farnesyltransferase adds a 15-carbon chain to a cysteine near the C-terminus of RAS, which is then cleaved by an endopeptidase before the new C-terminus is methylated by a methyltransferase.17 After these reactions, RAS localizes to the plasma membrane, where K-RAS and N-RAS, but not H-RAS, undergo an additional palmitoylation. Soon after the discovery of this pathway, inhibitors of the farnesyltrans-ferase were developed. These inhibitors are quite successful in inhibiting farnesyltransferase activity in vitro and in vivo, but they have been ineffective in inhibiting RAS in patients because of the alternative pathways for targeting K-RAS and N-RAS to the membrane.24,25 In the presence of farnesyl-transferase inhibitor, K-RAS and N-RAS become substrates for geranylgeranylation, the addition of a 20-carbon group that substitutes for farnesylation. Inhibitors of this process were also generated, but the combination of farnesylation and ger-anylgeranylation inhibitors results in high levels of cytotox-icity, most likely because of other targets of farnesylation and geranylgeranylation.25 Despite the lack of success of farne-syltransferase inhibitors, the endopeptidase and methyltrans-ferase involved in RAS localization remain possible targets for this approach.

The inhibition of downstream RAS pathways has also been an area of active research for chemotherapeutic agents. The signal transduction machinery of the BRAF and PI-3 kinase pathways appears suitable for the development of small molecule inhibitions. In fact, inhibitors of the BRAF and MEF kinases have been developed and used in clinical trials, and although the compounds are successful in inhibiting their kinases, they generate only partial responses.24 More recent attempts to target downstream pathways are focusing on the PI-3 kinase pathway, but these attempts remain in their infancy.

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