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Blood, 15 May 2005, Vol. 105, No. 10, pp. 3995-4003.

Prepublished online as a Blood First Edition Paper on January 18, 2005; DOI

10.1182/blood-2004-09-3534.

Submitted September 14, 2004

Accepted January 9, 2005

PD166326, a novel tyrosine kinase inhibitor, has greater anti-leukemic

activity than imatinib in a murine model of chronic myeloid leukemia

C Wolff, Darren R Veach, P Tong, G Bornmann, Bayard

son, and L Ilaria*

Hamon Center for Therapeutic Oncology Research, University of Texas

Southwestern Medical Center, Dallas, TX, USA

Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering

Cancer Center, New York, NY, USA

Division of Hematology/Oncology, Department of Medicine, University of Texas

Southwestern Medical Center, Dallas, TX, USA; Hamon Center for Therapeutic

Oncology Research, University of Texas Southwestern Medical Center, Dallas,

TX, USA

Imatinib mesylate is highly effective in newly diagnosed chronic myeloid

leukemia (CML), but BCR/ABL-positive progenitors persist in most

imatinib-treated CML patients, 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 anti-leukemic 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 anti-leukemic activity in vivo. Seventy percent of

PD166326-treated mice achieved a WBC less than 20 000/µL at necropsy,

compared with only 8% of imatinib-treated animals. Further, two-thirds of

PD166326-treated animals had complete resolution of splenomegaly, compared

to none of the imatinib-treated animals. Consistent with its more potent

anti-leukemic effect in vivo, PD166326 was also superior to imatinib 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-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

anti-leukemic activity. Clinical development of PD166326 or a related

analogue may lead to more effective drugs for the treatment of de novo and

imatinib-resistant CML.