Applying the discovery of the Philadelphia chromosome
Daniel W. Sherbenou, Brian J. Druker
Daniel W. Sherbenou, Brian J. Druker
View: Text | PDF
Review Series

Applying the discovery of the Philadelphia chromosome

Abstract

The identification of the Philadelphia chromosome in cells from individuals with chronic myelogenous leukemia (CML) led to the recognition that the BCR-ABL tyrosine kinase causes CML. This in turn led to the development of imatinib mesylate, a clinically successful inhibitor of the BCR-ABL kinase. Incorporating the use of markers of BCR-ABL kinase inhibition into clinical trials led to the realization that imatinib-resistant kinase domain mutations are the major cause of relapse during imatinib therapy and the subsequent development of new inhibitors to treat CML patients. The development of imatinib validates an emerging paradigm in cancer, in which a tumor is defined by genetic abnormalities and effective therapies are developed that target events critical to the growth and survival of a specific tumor.

Authors

Daniel W. Sherbenou, Brian J. Druker

×

Figure 3

Magnified views into the active sites of the ABL kinase domain in complex with imatinib (A) and dasatinib (B).

Options: View larger image (or click on image) Download as PowerPoint
Magnified views into the active sites of the ABL kinase domain in comple...
The two compounds have very different modes of binding to the kinase, with dasatinib more confined to the ATP-binding pocket than imatinib. In addition, imatinib binds the inactive and dasatinib the active conformations, with opposite orientations of the catalytic Glu-Phe-Gly amino acid residues (shown in light blue stick format). In the dasatinib structure, the glutamic acid of the Glu-Phe-Gly motif that coordinates a Mg2+ ion during catalysis is oriented properly for catalysis, whereas in the imatinib structure this residue points away from the active site. Both inhibitors reside in close proximity to the T315 residue. The side chain atoms of the residues susceptible to resistant mutations for each inhibitor are shown in green and inhibitor atoms shown in yellow stick format (nitrogen, dark blue; oxygen, red; sulfur, orange; chlorine, hot pink). The P-loop (residues 244–255) is shown in magenta and the activation loop (residues 381–402) is shown in light blue. (A) PDB entry 1IEP (24). (B) PDB entry 2GQG (78). The figure was created using PyMol (http://pymol.sourceforge.net/).