The interplay of structural information and functional studies in kinase drug design: insights from BCR-Abl.
As an inhibitor of the tyrosine kinase activity of the BCR-Abl oncoprotein, imatinib sets a new paradigm for the treatment of cancer with molecularly targeted therapies. Subsequent structural studies have provided in depth knowledge of how this antileukaemia drug interacts with the catalytic site of the enzyme and allowed the rationalisation of mechanisms of drug-resistance which can lead to patient relapse. This understanding has facilitated the design of new inhibitors of BCR-Abl, as well as the discovery of inhibitors of many other kinases. As structural information accumulates for more of the 518 kinases encoded within the human genome, the design of many more highly selective, well-tolerated kinase inhibitors should be possible.
Eck
Michael J
MJ
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Manley
Paul W
PW
D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D001549:Benzamides; D015195:Drug Design; D066246:ErbB Receptors / Q000737:chemistry / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D010879:Piperazines / Q000737:chemistry / Q000627:therapeutic use; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000737:chemistry / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D048493:Proto-Oncogene Proteins B-raf