The Farnesyl Protein Transferase Inhibitor BZA-5B Blocks Farnesylation of Nuclear Lamins and p21^ras but Does Not Affect Their Function or Localization

Abstract

BZA-5B is a peptidomimetic inhibitor of protein farnesylation in mammalian cells. We have examined the specificity of this compound toward inhibition of farnesylation of p21^ras and the nuclear lamin proteins, prelamin A and lamin B. We have also used the Raney nickel cleavage technique in conjunction with radio-gas liquid chromatography to assess the ability of this compound to block total protein farnesylation. These studies show that BZA-5B blocks farnesylation of the lamin proteins with an IC₅₀ comparable to that seen for p21^ras. At a concentration in excess of 25 µm, 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 this compound. Yet, despite the potent and general inhibition of protein farnesylation, BZA-5B does not interfere with a variety of cellular functions expected to be farnesylation dependent, including cell growth and viability, assembly of the nuclear lamina, membrane association of p21^ras, and p21^ras-dependent differentiation of PC-12 cells in response to treatment with nerve growth factor.

The maintenance of farnesylation-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 ras transformation by BZA-5B is quite encouraging to its eventual development as an antimalignancy pharmaceutical.