BCR/ABL, the
oncoprotein responsible for
chronic myeloid leukemia (CML), transforms hematopoietic cells through both Ras-dependent and -independent mechanisms. Farnesyl
protein transferase inhibitors (FTIs) were designed to block mutant Ras signaling, but they also inhibit the growth of transformed cells with wild-type Ras, implying that other farnesylated targets contribute to FTI action. In the current study, the clinical candidate FTI
SCH66336 was characterized for its ability to inhibit BCR/ABL transformation. When tested against BCR/ABL-BaF3 cells, a murine cell line that is leukemogenic in mice,
SCH66336 potently inhibited soft
agar colony formation, slowed proliferation, and sensitized cells to apoptotic stimuli. Quantification of activated
guanosine triphosphate (
GTP)-bound
Ras protein and electrophoretic mobility shift assays for
AP-1 DNA binding showed that Ras effector pathways are inhibited by
SCH66336. However,
SCH66336 was more inhibitory than dominant-negative Ras in assays of soft
agar colony formation and cell proliferation, suggesting activity against targets other than Ras. Cell cycle analysis of BCR/ABL-BaF3 cells treated with
SCH66336 revealed G2/M blockade, consistent with recent reports that centromeric
proteins that regulate the G2/M checkpoint are critical farnesylated targets of FTI action. Mice injected intravenously with BCR/ABL-BaF3 cells developed acute
leukemia and died within 4 weeks with massive
splenomegaly, elevated white blood cell counts, and
anemia. In contrast, nearly all mice treated with
SCH66336 survived and have remained disease-free for more than a year. Furthermore,
SCH66336 selectively inhibited the hematopoietic colony formation of primary human CML cells. As an oral, nontoxic compound with a mechanism of action distinct from that of ABL
tyrosine kinase inhibition, FTI
SCH66336 shows promise for the treatment of BCR/ABL-induced
leukemia.