The success of kinase inhibitors, such as imatinib and gefitinib, has shown that the development of specific, targeted therapies for cancer is possible.
However, there have been many cases of drug resistance to imatinib observed in the clinic and this has consequences for the development of second-generation kinase inhibitors.
Current efforts are focused on characterizing the structural determinants of imatinib resistance observed in the clinic. These studies illustrate the importance of features such as the gatekeeper residue, the p-loop and the activation loop of protein kinases.
The design of more effective inhibitors based on this structural knowledge, combined with the development of multi-targeted kinase inhibitors that show improved efficacy, hold great promise for cancer therapy.
Selective inhibition of protein tyrosine kinases is gaining importance as an effective therapeutic approach for the treatment of a wide range of human cancers. However, as extensively documented for the BCR–ABL oncogene in imatinib-treated leukaemia patients, clinical resistance caused by mutations in the targeted oncogene has been observed. Here, we look at how structural and mechanistic insights from imatinib-insensitive Bcr–Abl have been exploited to identify second-generation drugs that override acquired target resistance. These insights have created a rationale for the development of either multi-targeted protein kinase inhibitors or cocktails of selective antagonists as antitumour drugs that combine increased therapeutic potency with a reduced risk of the emergence of molecular resistance.
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The authors wish to thank D. Brehmer for stimulating discussions and his contributions to the illustrations in figure 2 and figure 5. The work carried out in the laboratory of H.D. is supported by a grant from the German Ministry for Education and Research (Bundesministerium für Bildung und Forschung, BMBF).
H.D. is an employee of Axxima Pharmaceuticals AG.A.U. and H.D. are shareholders in Axxima Pharmaceuticals AG.
- CHRONIC MYELOID LEUKAEMIA
(CML). A myeloproliferative disorder that is characterized by a distinctive cytogenetic abnormality, the Philadelphia (Ph) chromosome.
The fusion gene that results from the chromosomal translocation that causes the Abelson protein tyrosine kinase gene to fuse with the BCR gene on the so-called Philadelphia (Ph) chromosome.
- BLAST CRISIS
The aggressive phase of chronic myelogenous leukaemia evidenced by an increased number of immature white blood cells in the circulating blood.
- INDUCED-FIT MECHANISM
The interaction between a protein and ligand in which the binding of the ligand alters the conformation of the protein's active site to best accommodate binding of the ligand.
- IDIOPATHIC HYPER-EOSINOPHILIC SYNDROME
The presence of prolonged eosinophilia without an identifiable underlying cause and with evidence of end-organ dysfunction.
- INTERSTITIAL CHROMOSOMAL DELETION
Loss of material from within one of the chromosome arms.
- HUMAN KINOME
The collection of genes in the human genome encoding kinases.
- DUAL-SPECIFICITY KINASE INHIBITOR
An inhibitor that specifically interferes with two distinct protein kinase activities.
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Daub, H., Specht, K. & Ullrich, A. Strategies to overcome resistance to targeted protein kinase inhibitors. Nat Rev Drug Discov 3, 1001–1010 (2004). https://doi.org/10.1038/nrd1579
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