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[Cancer Research 60, 3127-3131, June 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

The Pyrido[2,3-d]pyrimidine Derivative PD180970 Inhibits p210Bcr-Abl Tyrosine Kinase and Induces Apoptosis of K562 Leukemic Cells1

Jay F. Dorsey, Richard Jove, Alan J. Kraker and Jie Wu2

Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute [J. F. D., R. J., J. W.] and the Departments of Medical Microbiology and Immunology [J. F. D., J. W.], Biochemistry and Molecular Biology [R. J., J. W.], University of South Florida College of Medicine, Tampa, Florida 33612; Department of Cancer Research, Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105 [A. J. K.]

PD180970 is a novel pyrido[2,3-d]pyrimidine class of ATP-competitive inhibitor of protein tyrosine kinases. We found that PD180970 inhibited in vivo tyrosine phosphorylation of p210Bcr-Abl (IC50 = 170 nM) and the p210Bcr-Abl substrates Gab2 and CrkL (IC50 = 80 nM) in human K562 chronic myelogenous leukemic cells. In vitro, PD180970 potently inhibited autophosphorylation of p210Bcr-Abl (IC50 = 5 nM) and the kinase activity of purified recombinant Abl tyrosine kinase (IC50 = 2.2 nM). Incubation of K562 cells with PD180970 resulted in cell death. Results of nuclear staining, apoptotic-specific poly(ADP-ribose) polymerase cleavage, and annexin V binding assays indicated that PD180970 induced apoptosis of K562 cells. In contrast, PD180970 had no apparent effects on the growth and viability of p210Bcr-Abl-negative HL60 human leukemic cells. Thus, PD180970 is among the most potent inhibitors of the p210Bcr-Abl tyrosine kinase, which is present in almost all cases of human chronic myelogenous leukemia. These findings indicate that PD180970 is a promising candidate as a novel therapeutic agent for Bcr-Abl-positive leukemia.




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