Comparison of effects of the tyrosine kinase inhibitors AG957, AG490, and STI571 on BCR-ABL-expressing cells, demonstrating synergy between AG490 andSTI571

ST1571 (formerly CGP57148) and AG957 are small molecule inhibitors of the p rotein tyrosine kinase (PTK) p145(abl) and its oncogenic derivative p210(bc r-abl). AG490 is an inhibitor of the PTK Janus kinase 2 (JAK2). No direct c omparison of these inhibitors has previously been reported, so this study c ompared their effects on factor-dependent FDC-P1, 32D, and MO7e cells and t heir p210(bcr-abl)-expressing factor-independent derivatives. ST1571 was a more potent inhibitor of H-3-thymidine incorporation in p210(bcr-abl)-expre ssing cells than was AG957, and it showed superior discrimination between i nhibitory effects on parental cell lines and effects on their p210(bcr-abl) -expressing derivatives. Assays performed with and without growth factor de monstrated that ST1571 but not AG957 reversed the p210(bcr-abl)-driven fact or independence of cell lines. p210(bcr-abl)-expressing cells were less sen sitive to AG490 than to AG957 or ST1571. However, for p210(bcr-abl)-express ing clones from all 3 cell lines, synergistic inhibition was demonstrated b etween ST1571 and concentrations of AG490 with no independent inhibitory ef fect. Inhibition of nucleic acid synthesis with AG957 treatment was associa ted with reduced cell numbers, reduced viability, and small pyknotic apopto tic cells. At concentrations of ST1571 that reversed the p210(bcr-abl) fact or-independent phenotype, ST1571 treatment and growth factor deprivation to gether were sufficient to induce apoptosis. This study concludes that, for the cell lines studied, (1) ST1571 is a more potent and more selective inhi bitor of a p210(bcr-abl)-dependent phenotype than AG957; (2) AG490 synergiz es with ST1571 to enhance its inhibitory effect on p210(bcr-abl)- driven pr oliferation; and (3) the combination of p210(bcr-abl)-tyrosine kinase inhib ition and growth factor signal withdrawal can be sufficient to induce apopt otic death of transformed cells. (Blood. 2001;97:2008-2015) (C) 2001 by The American Society of Hematology.