THE FARNESYL-PROTEIN TRANSFERASE INHIBITOR BZA-5B BLOCKS FARNESYLATION OF NUCLEAR LAMINS AND P21(RAS) BUT DOES NOT AFFECT THEIR FUNCTION ORLOCALIZATION

BZA-5B is a peptidomimetic inhibitor of protein farnesylation in mamma lian cells, We have examined the specificity of this compound toward i nhibition of farnesylation of p21(ras) and the nuclear lamin proteins, pre-lamin A and lamin B. We have also used the Raney nickel cleavage technique in conjunction with radio-gas liquid chromatography to asses s the ability of this compound to block total protein farnesylation. T hese studies show that BZA-5B blocks farnesylation of the lamin protei ns with an IC50 comparable to that seen for p21(ras). At a concentrati on in excess of 25 mu M, BZA-5B inhibits all protein farnesylation in CHO-K1 cells below the limits of detection. Furthermore, we found that after a 2-day exposure to high concentrations of BZA-5B, CHO-K1 cell lines exhibit no loss in sensitivity to inhibition of prenylation by t his compound. Yet, despite the potent and general inhibition of protei n farnesylation, BZA-5B does not interfere with a variety of cellular functions expected to be farnesylation dependent, including cell growt h and viability, assembly of the nuclear lamina, membrane association of p2l(ras), and p21(ras)-dependent differentiation of PC-12 cells in response to treatment with nerve growth factor. The maintenance of far nesylation-dependent events in the presence of BZA-5B stands in marked contrast to the inhibition of the oncogenic ras-mediated transformed phenotype that has been observed with this compound and other farnesyl protein transferase inhibitors. This specificity for inhibition of ra s transformation by BZA-5B is quite encouraging to its eventual develo pment as an antimalignancy pharmaceutical.