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Preclinical Evaluation of an Inhibitor of
the ABL Tyrosine Kinase as a Therapeutic Agent
for Chronic Myelogenous Leukemia
B.J. Druker, E. Buchdunger, S. Ohno-Jones, N.B. Lydon
Oregon Health Sciences University, Portland, OR; Novartis Pharmaceuticals,
Basel, Switzerland; Kinetix Pharmaceuticals, Medford, MA
p210BCR-ABL, present in virtually all cases of chronic myelogenous leukemia
(CML) is derived from a hybrid gene created by the Philadelphia chromosome
translocation. This hybrid gene has been shown to cause a CML-like syndrome in
mice and is capable of transforming immature hematopoietic cells in vitro. The
hybrid BCR-ABL protein has elevated tyrosine kinase activity compared with c-
ABL, and the tyrosine kinase activity of ABL is required for the transforming
function of the BCR-ABL fusion protein. Using the known structure of the ATP
binding site of protein kinases, a series of potentially inhibitory compounds were
synthesized, and CGP 57148 was found to be a potent and specific inhibitor of the
ABL protein tyrosine kinase. Using factor-dependent myeloid cells (32D and
M07) and derivatives expressing p210BCR-ABL, we demonstrated specific
killing of BCR-ABL-expressing cells by CGP 57148. Similar cytotoxicity has been
observed using a variety of Philadelphia chromosome-positive cell lines and cells
expressing the pl85BCR-ABL protein associated with acute lymphoblastic
leukemia. In vivo, antitumor activity of the compound has been validated in
syngeneic mice inoculated with BCR-ABL-expressing cells. In colony-forming
assays of peripheral blood or bone marrow from patients with CML, there was a
60-80% decrease in the number of colonies formed in the presence of CGP 57148
but minimal inhibition of colony formation by hematopoietic cells from non-CML
patients or a BCR-ABL-negative CML patient. This compound may be useful in
the treatment of CML and other BCR-ABL-positive leukemias. Phase I clinical
trials in CML patients resistant to interferon-alpha are underway.
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