Abstract
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.
MeSH terms
-
Antineoplastic Agents / chemistry
-
Antineoplastic Agents / therapeutic use
-
Benzamides
-
Drug Design*
-
ErbB Receptors / chemistry
-
ErbB Receptors / metabolism
-
Fusion Proteins, bcr-abl / antagonists & inhibitors*
-
Humans
-
Imatinib Mesylate
-
Models, Molecular
-
Molecular Structure
-
Neoplasms / drug therapy
-
Neoplasms / enzymology
-
Piperazines / chemistry
-
Piperazines / therapeutic use
-
Protein Conformation
-
Protein Kinase Inhibitors / chemistry*
-
Protein Kinase Inhibitors / therapeutic use
-
Protein-Tyrosine Kinases / antagonists & inhibitors*
-
Proto-Oncogene Proteins B-raf / chemistry
-
Proto-Oncogene Proteins B-raf / metabolism
-
Pyrimidines / chemistry
-
Pyrimidines / therapeutic use
Substances
-
Antineoplastic Agents
-
Benzamides
-
Piperazines
-
Protein Kinase Inhibitors
-
Pyrimidines
-
Imatinib Mesylate
-
ErbB Receptors
-
Protein-Tyrosine Kinases
-
Fusion Proteins, bcr-abl
-
Proto-Oncogene Proteins B-raf