Imatinib: Difference between revisions

Chronic Myelogenous Leukemia (CML) results from a gene defect in a haematological stem cell (HSC). Compared to the tightly regulated c-Abl kinase, BCR-Abl has a truncated auto-regulatory domain, leading to constitutive activation of its tyrosine kinase activity. The result of this nearly limitless activation is unregulated phosphorylation of downstream receptors leading to uncontrolled growth and survival of leukemic cells. Like many other receptor tyrosine kinases, Abl is at an equilibrium between two states, an active state and an auto-regulated inactive state. Imatinib functions by binding and stabilizing the inactive conformation of Abl, in which the well known "DFG triad" is in the "out" conformation. In the DFG out conformation the residues surrounding Tyr 393 disrupt the ATP binding site, inhibiting Abl's kinase activity. A critically important residue, Thr 315, is known as the gatekeeper residue. In the inactive DFG out conformation, Thr 315 shifts to allow binding of Imatinib. It is this Thr 315 that is believed to give Imatinib its remarkable binding specificity. Although the DFG-out conformation has been seen in other kinases like B-Raf, p38, KDR, Flt-3, and insulin receptor kinase, Imatinib does not bind any of these kinases. The primary reason is appears to be that all of these kinases have a residue at position 315 that is larger than the threonine present in Abl. These larger residues block the pocket formed by the DFG out conformation in which Imatinib binds, preventing Imatinib from stabilizing these compounds.<ref>PMID:17164530</ref> Interestingly, both KIT and PDGFR have nearly identical DFG out conformations and have the same Thr residue at this gatekeeper position, explaining how Imatinib binds and inhibits these proteins commonly involved in Gastrointestinal Stromal [[Cancer|Tumors]]. In Abl, Imatinib is bound by residues ____, firmly securing the inhibitor in place and stabilizing the inhibited conformation of the kinase. <ref>doi:10.1107/S0907444906047287</ref>