Structural Mechanism for STI-571 Inhibition of Abelson Tyrosine Kinase

Abstract

The inadvertent activation of the Abelson tyrosine kinase (Abl) causes chronic myelogenous leukemia (CML). A small-molecule inhibitor of Abl (STI-571) is effective in the treatment of CML. We report the crystal structure of the catalytic domain of Abl, complexed to a variant of STI-571. 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 mechanisms of individual protein kinases can achieve both high affinity and high specificity.

The Src tyrosine kinase Hck is required for Tel-Abl- but not for Tel-Jak2-induced cell transformation

“…Imatinib mesylate suppresses Hck, Stat5, Akt, Erk1/2 phosphorylations As the Src inhibitors PP2 and SU6656 affected the phosphorylation of Tel-Abl, we therefore determined Tel-Abl induces oncogenic signalling via Hck C Pecquet et al whether Tel-Abl targets Hck by using the Abl kinase inhibitor imatinib mesylate (STI-571, Gleevec) (Schindler et al, 2000). Effects of imatinib mesylate on the Tel-Abl activity based on Western blot and biological analysis were determined ( Figure 5).…”

Effects of imatinib mesylate (STI571, Glivec) on the pharmacokinetics of simvastatin, a cytochrome P450 3A4 substrate, in patients with chronic myeloid leukaemia

“…Imatinib mesylate (STI571, Glivec s , Gleevec s -Novartis, Basel, Switzerland) is a potent competitive inhibitor of the tyrosine kinases associated with ABL Druker et al, 1996), KIT (Buchdunger et al, 2000;Heinrich et al, 2000), PDGFr (Buchdunger et al, , 2000 and ARG (Okuda et al, 2001), which impedes the interaction of ATP with the SH1 domain of these proteins (Schindler et al, 2000), thereby inhibiting the phosphorylation of downstream target proteins. Imatinib is a phenylaminopyrimidine derivative and represents the first of a new class of drugs known as signal transduction inhibitors.…”

Novel therapies for chronic myelogenous leukemia

“…STI 571 recognizes a distinct characteristic inactive conformation of the activation loop of the ABL-TK, and binds to it with a high degree of specificity, resulting in inhibition of autophosphorylation and inhibition of substrate phosphorylation [144].…”