Imatinib mesylate is highly effective in newly diagnosed
chronic myeloid leukemia (CML), but BCR/ABL (breakpoint cluster region/abelson murine
leukemia)-positive progenitors persist in most patients with CML treated with
imatinib mesylate, indicating the need for novel therapeutic approaches. In this study, we have used the murine CML-like
myeloproliferative disorder as a platform to characterize the pharmacokinetic, signal transduction, and antileukemic properties of
PD166326, one of the most potent members of the pyridopyrimidine class of
protein tyrosine kinase inhibitors. In mice with the CML-like disease,
PD166326 rapidly inhibited Bcr/Abl
kinase activity after a single oral dose and demonstrated marked antileukemic activity in vivo. Seventy percent of PD166326-treated mice achieved a white blood cell (WBC) count less than 20.0 x 10(9)/L (20,000/microL) at necropsy, compared with only 8% of
imatinib mesylate-treated animals. Further, two thirds of PD166326-treated animals had complete resolution of
splenomegaly, compared with none of the
imatinib mesylate-treated animals. Consistent with its more potent antileukemic effect in vivo,
PD166326 was also superior to
imatinib mesylate in inhibiting the constitutive
tyrosine phosphorylation of numerous
leukemia-cell
proteins, including the src family member Lyn.
PD166326 also prolonged the survival of mice with
imatinib mesylate-resistant CML induced by the Bcr/Abl mutants P210/H396P and P210/M351T. Altogether, these findings demonstrate the potential of more potent Bcr/Abl inhibitors to provide more effective antileukemic activity. Clinical development of
PD166326 or a related analog may lead to more effective drugs for the treatment of de novo and
imatinib mesylate-resistant CML.