Molecular Pathogenesis As Guide For Novel Therapies

Formation of the BCR-ABL gene and its chimeric protein is at the core of the pathogenesis of CML. The interaction of BCR-ABL with other cellular proteins and the elements of multiple and complex signaling pathways are increasingly recognized

Figure 4-5. The dissection of the BCR-ABL signaling cascade has provided many new targets for therapeutic intervention at almost every level of the pathogenesis of CML. Most promising are the the BCR-ABL tyrosine kinase inhibitors such as STI-571 that are currently used in clinical trials in patients with CML.

Figure 4-5. The dissection of the BCR-ABL signaling cascade has provided many new targets for therapeutic intervention at almost every level of the pathogenesis of CML. Most promising are the the BCR-ABL tyrosine kinase inhibitors such as STI-571 that are currently used in clinical trials in patients with CML.

as potential targets for novel therapeutic agents (Figure 4-5).169 Most prominent among these agents are tyrosine kinase inhibitors with an exceptional affinity for ABL. Ima-tinib merylate (formerly known as STI-571 or CGP57148B), a small 2-phenylaminopyridimine compound, has been identified as the most promising member of these small molecules.170 It also inhibits the kinase activity of c-KIT and PDGFR, but none of more than 50 other kinases including serine/threonine kinases that have been screened.171 STI-571 binds to the ATP-binding loop of the ABL protein. This sequence of ABL, like in many other kinases, must have a phosphate group added before it can phosphorylate other proteins. This process changes the conformation of ABL to open it up so that it can bind ATP and the target protein. Although the "active" conformation of this sequence is almost identical in other kinases, imatinib locks ABL in its inactive conformational state that differs among kinases and best explains the specificity of imatinib.172 This mode of action serves as an example of how enzyme inhibitors can be identified that are specific for their target and can thus be used to knock out part of a specific signal transduction pathway that contributes to the leukemic phenotype. Many pep-tides, small molecules, and other agents are being identified with the potential to inhibit the chain of transforming events of BCR-ABL at virtually every level from transcription to activation of intracellular signaling pathways.173-175 However, a great amount of redundancy exists within the BCR-ABL signaling network, and additional hits are operative in transformation of the disease, so that inhibition of a single pathway may only have limited efficacy in abrogating leukemogenesis.

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