Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.

@article{Schindler2000StructuralMF,
  title={Structural mechanism for STI-571 inhibition of abelson tyrosine kinase.},
  author={Thomas E. Schindler and William G. Bornmann and Patricia Pellicena and W. Todd Miller and Bayard Clarkson and John Kuriyan},
  journal={Science},
  year={2000},
  volume={289 5486},
  pages={
          1938-42
        }
}
The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML. [] Key Result Critical to the binding of STI-571 is the adoption by the kinase of an inactive conformation, in which a centrally located "activation loop" is not phosphorylated. The conformation of this loop is distinct from that in active protein kinases, as well as in the inactive form of the closely related Src kinases. These results suggest that compounds that exploit the distinctive inactivation…
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STI-571: an anticancer protein-tyrosine kinase inhibitor.

  • R. Roskoski
  • Biology, Chemistry
    Biochemical and biophysical research communications
  • 2003

Structural Basis for the Autoinhibition of c-Abl Tyrosine Kinase

Breakthroughs and Views STI-571: an anticancer protein-tyrosine kinase inhibitor q

STI-571 (imatinib, Gleevec, Glivec, CGP 57148) is an inhibitor of the Abl group of protein-tyrosine kinases, which results from the fusion of the BCR and ABL genes that result from the reciprocal chromosomal translocation that forms the Philadelphia chromosome.

Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases.

A Myristoyl/Phosphotyrosine Switch Regulates c-Abl

A Novel Mode of Gleevec Binding Is Revealed by the Structure of Spleen Tyrosine Kinase*

The x-ray structure of the unphosphorylated form of the kinase catalytic domain of Syk is determined, suggesting the existence of two distinct Gleevec binding modes: an extended, trans-conformation characteristic of tight binding to the inactive conformation of a protein kinase and a second compact, cis-conform characteristic of weakerbinding to the active conformation.

Insights into selectivity of STI571 [GleevecTM] from X-ray crystallography

Comparison of the non-selective conformation of Gleevec with a second structure of STi571 bound to a FAK mutant, which has an increased affinity for the inhibitor, illuminates the structural features of the kinase active site that confer STI571 selectivity.

Crystal structure of an SH2-kinase construct of c-Abl and effect of the SH2 domain on kinase activity.

An important function of the SH2-N-lobe interaction might be to help disassemble the auto-inhibited conformation of c-Abl and promote processive phosphorylation, rather than substantially stimulate kinase activity.

Sti‐571 in Chronic Myelogenous Leukaemia

This review addresses the issue of CML resistance to STI-571, a 2-phenylaminopyrimidine, which is a highly selective inhibitor of the protein tyrosine kinase family, which includes BCR–ABL protein, the platelet-derived growth factor (PDGF) receptor and the c-kit receptor.

Rapid synthesis of Abelson tyrosine kinase inhibitors using click chemistry.

This article has, for the first time, developed an efficient method for the construction of small molecule-based bisubstrate inhibitors of Abl kinase using click chemistry, a few of which have comparable potency to Imatinib against Abl.
...

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