Lessons learned from the development of an Abl tyrosine kinase inhibitor for chronic myelogenous leukemia

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阅读量：

181

作者：

BJ Druker，NB Lydon

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摘要：

Protein kinases are a large family of homologous pro- teins comprising 2 major subfamilies, the protein ser- ine/threonine kinases and protein tyrosine kinases (PTKs). Protein kinases function as components of sig- nal transduction pathways, playing a central role in diverse biological processes such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases with abnormalities in these signaling pathways is considered a promising approach for drug development. Because of their dereg- ulation in human cancers, Bcr-Abl, EGFR, HER2, and protein kinase C (PKC), were among the first protein kinases considered as targets for the development of selective inhibitors. Subsequently, as protein kinases have been implicated in more human cancers (1), drug- discovery efforts have been extended and several first- generation small-molecule inhibitors are now in vari- ous stages of development. A selection of these agents is shown in Table 1. Based on its clear disease association, we saw the Bcr- Abl tyrosine kinase as an ideal target for validating the clinical utility of protein kinase inhibitors. Here, we dis- cuss our experience in the preclinical and clinical devel- opment of a Bcr-Abl inhibitor as a therapeutic agent for chronic myelogenous leukemia (CML), and we consider how this experience and other recent advances in the field could contribute to drug development for other diseases. The Bcr-Abl kinase as a target

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关键词：

osteoporosis glucocorticoid vitamin D HRT bisphosphonates

DOI：

10.1172/JCI9083

被引量：

3679

年份：

2000