[Inhibitors of farnesyl transferase in oncology: from basic research to pharmaceutical research]

Advances in medical oncology have been obtained with compounds having new structure/mechanism of action. Pharmaceutical research is largely focused on "prospective" targets identified by basic science such as the oncogenic signal transduction pathways. Ras proteins stand as converging targets that could be blocked by different approaches including inhibition of the isoprenylation of the proteins. Many academic institutions and pharmaceutical companies have embarked on the research of farnesyl transferase inhibitors. Two approaches have been developed: 1) random screening of compounds from natural/synthetic origin; 2) synthesis of compounds able to mimic the C-terminal tetrapeptidic "CAAX box" and to inhibit consequently the critical step of farnesylation. This peptidomimetic approach has been successfull since active and specific inhibitors of Ras proteins farnesylation have been synthesized in the nM range. However, several major drawbacks have been identified: in particular, most of the time, the preclinical evaluation has been done with biochemical and biological materials implicating the activated Ha-ras oncogene (very unfrequently activated in human tumors) instead of the activated Ki-ras oncogene which is the relevant target in human carcinomas. This has resulted in the selection of compounds with preferential activity on Ha-ras tumors. Nevertheless, evidence has been now generated that inhibition of farnesyl transferase of ras proteins can lead to significant experimental antitumor effects. The most convincing data are those obtained with the Merck inhibitor L739,749 which is able to cause tumor regressions of carcinomas in transgenic mice.