PI-3 kinase activation is essential for the BCR/ABL-mediated transformation of cells. PI-3 kinase is a het-erodimer consisting of catalytic (p110) and regulatory (p85) segments. BCR/ABL interacts with the p85 subunit. Two PI-3 kinase inhibitors are currently in clinical development. Wortmannin and LY294002 are active compounds and synergize with imatinib in vitro.38 39 Wortmannin is a naturally occurring compound and is highly unstable in solution, making it a challenging compound to develop clinically.
Several downstream effectors in this PI-3 kinase pathway have been identified. One is m-TOR, which is involved in the phosphorylation of several signaling proteins, including the S6 ribosomal protein, an important target of BCR/ABL.40 Inhibitors of m-TOR, such as rapamycin, have been attractive as possible therapeutic agents in CML. These agents have already undergone phase I/II clinical testing in a variety of other tumors and are currently beginning clinical trials in CML.41
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