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

  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},
  volume={289 5486},
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…

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.



Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors.

A new class of protein tyrosine kinase inhibitors was identified that is based on an oxindole core (indolinones). Two compounds from this class inhibited the kinase activity of fibroblast growth

An intramolecular SH3-domain interaction regulates c-Abl activity

Evidence is presented for an intramolecular inhibitory interaction of the SH3 domain with the catalytic domain and with the linker between the SH2 and catalyticdomain (SH2-CD linker) that activates and inhibits c-Abl.

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

A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr–Abl fusion protein and it was found that this compound may be useful in the treatment of bcr–abl–positive leukemias.

N‐terminal mutations activate the leukemogenic potential of the myristoylated form of c‐abl.

The smallest of these deletions, delta XB, efficiently transforms lymphoid cells in vitro and causes leukemia in vivo demonstrating that gag sequences are not necessary for abl‐induced leukemogenesis.

Autoregulatory Mechanisms in Protein-tyrosine Kinases*

The recent crystallographic structures of several members of both the RTK and NRTK families, together with extensive biochemical studies, afford an understanding at the molecular level of the autoregulation mechanisms to which PTKs are subject.