Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells

  title={Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr–Abl positive cells},
  author={Brian J. Druker and S Tamura and Elisabeth Buchdunger and Sayuri Ohno and Gerald M. Segal and Sean W. Fanning and J{\"u}rg Zimmermann and Nicholas Lydon},
  journal={Nature Medicine},
The bcr–abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr–Abl fusion protein. Cellular proliferation and tumor formation by Bcr–Abl–expressing cells were specifically inhibited by this compound. In colony–forming assays of peripheral blood or bone marrow from patients with CML, there was a 92… 
Inhibition of the Bcr-Abl tyrosine kinase as a therapeutic strategy for CML
An inhibitor of the Bcr-Abl kinase would be predicted to be an effective and selective therapeutic agent for CML.
Allosteric inhibitors of Bcr-abl–dependent cell proliferation
The discovery of a new class of Bcr-abl inhibitors is reported using an unbiased differential cytotoxicity screen of a combinatorial kinase-directed heterocycle library and it is proposed that this newclass of compounds inhibits BCr-abl kinase activity through an allosteric non-ATP competitive mechanism.
Status of bcr-abl tyrosine kinase inhibitors in chronic myelogenous leukemia
In preclinical studies, STI571 (formerly CGP57148B), an abl-specific, tyrosine kinase inhibitor, selectively killed bcr-abl-expressing cells both in vitro and in vivo.
Inhibition of the ABL kinase activity blocks the proliferation of BCR/ABL+ leukemic cells and induces apoptosis.
The activity of CGP57148B on the spontaneous proliferation of both fresh and cultured, leukemic and normal, BCR/ABL positive and negative cells, and its mechanism of action are investigated to support the use of this molecule in initial clinical studies.
Selective Killing of BCR-ABL Positive Cells with a Specific Inhibitor of the ABL Tyrosine Kinase
Chronic myelogenous leukemia (CML) is a malignancy of the pluripotent hematopoietic stem cell. This disease accounts for 15–20% of all leukemias with an annual incidence of between 1 to 2 cases per
Bcr-Abl-mediated resistance to apoptosis is independent of constant tyrosine-kinase activity
It is proposed that secondary antiapoptotic signals are entirely responsible for the resistance of Bcr-Abl-positive cells, which are extremely resistant to apoptosis in the absence of tyrosine-kinase activity.
The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells.
CGP57148B, a 2-phenylaminopyrimidine derivative, has been shown to selectively inhibit the tyrosine kinase of ABL and BCR-ABL and it is concluded that this new agent may have significant therapeutic applications.
Mechanisms of Transformation by the BCR/ABL Oncogene
Mechanisms of transformation by the BCR/ABL oncogene and opportunities for clin-ical intervention with specific signal transduction inhibitors such as STI-571 in CML are described.
c-Kit Receptor Tyrosine Kinases Characterization of Potent Inhibitors of the Bcr-Abl and the Updated
These compounds are potent inhibitors of both the Bcr-Abl and c-kit receptor tyrosine kinases and deserve further study as potential treatments for both CML and for diseases in which c-Kit has a role.


Inhibition of apoptosis by BCR-ABL in chronic myeloid leukemia.
The decreased rate of programmed cell death appears to be the primary mechanism by which BCR-ABL effects expansion of the leukemic clone in CML.
Activation of the Abelson tyrosine kinase activity is associated with suppression of apoptosis in hemopoietic cells.
A chromosomal translocation uniquely associated with chronic myeloid leukemia leads to the formation of a chimeric gene, bcr-abl, on the Philadelphia chromosome that can specifically suppress apoptosis.
Tyrosine kinase activity and transformation potency of bcr-abl oncogene products.
Analysis of tyrosine kinase activity and quantitative measurement of transformation potency in a single-step assay indicate that variation in bcr exon contribution results in a functional difference between p210bCr-abl and p185bcr-abl proteins.
The SH2 domain of ABL is not required for factor-independent growth induced by BCR-ABL in a murine myeloid cell line.
The results indicate that the SH2 domain of BCR-ABL is not required for the induction of growth factor independence and is not necessary for the association of B CR-ABl with rasGAP or SHC, and myeloid cells expressing this mutant lack the tyrosine phosphorylation of a 62-kDa ras GAP associated protein.
Crkl is the major tyrosine-phosphorylated protein in neutrophils from patients with chronic myelogenous leukemia.
The Philadelphia chromosome (Ph1), detected in virtually all cases of chronic myelogenous leukemia (CML), is formed by a reciprocal translocation between chromosome 9 and 22 that fuses Bcr-encoded
Lineage-specific requirement of c-abl function in normal hematopoiesis.
Data show that c-abl is critical in normal myelopoiesis and may explain the relatively selective expansion of leukocytes in patients with chronic myelogenous leukemia.
Evidence for regulation of the human ABL tyrosine kinase by a cellular inhibitor.
The combined results indicate that inhibition of ABL activity is reversible and suggest that a cellular component interacts noncovalently with ABL to inhibit its autophosphorylation.
Activation of the c-Abl tyrosine kinase in the stress response to DMA-damaging agents
It is shown that ionizing radiation activates c-Abl and this findings indicate that c-abl is involved in the stress response to DNA-damaging agents.
Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein.
  • G. Daley, D. Baltimore
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1988
It is established that P210bcr/abl can transform hematopoietic cell types to tumorigenicity and for autocrine production of interleukin 3 by factor-independent cell lines was found.