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Nat Rev Drug Discov. 2004 Dec;3(12):1001-10.

Strategies to overcome resistance to targeted protein kinase inhibitors.

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Axxima Pharmaceuticals AG, Max-Lebsche-Platz 32, 81377 M√ľnchen, Germany.


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.

[Indexed for MEDLINE]

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