Lessons learned from the development of an abl tyrosine kinase inhibitor for chronic myelogenous leukemia.
نویسندگان
چکیده
teins comprising 2 major subfamilies, the protein serine/threonine kinases and protein tyrosine kinases (PTKs). Protein kinases function as components of signal 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 deregulation 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), drugdiscovery efforts have been extended and several firstgeneration small-molecule inhibitors are now in various stages of development. A selection of these agents is shown in Table 1. Based on its clear disease association, we saw the BcrAbl tyrosine kinase as an ideal target for validating the clinical utility of protein kinase inhibitors. Here, we discuss our experience in the preclinical and clinical development 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.
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ورودعنوان ژورنال:
- The Journal of clinical investigation
دوره 105 1 شماره
صفحات -
تاریخ انتشار 2000