Mechanism of action of a novel tyrosine kinase inhibitor

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Chronic myelogenous leukemia (CML) is the most common myeloproliferative disorder and accounts for 20% of all leukemias. Notably, it is a disease in which identification of a molecular defect has facilitated novel therapeutic strategies. .In over 95% of CML cases, the c-ABL gene from chromosome 9 translocates and fuses with the BCR gene on chromosome 22, giving rise to the p210bcr/abl protein tyrosine kinase. Inhibition of p210bcr/abl kinase activity represents a pharmacological goal. STI571 is the first of these tyrosine kinase inhibitors to be introduced into the clinic. However, ongoing clinical evaluation of STI571 reveals that continuous dosing is required for the optimal efficacy of this drug. Also, preliminary reports indicate that patients with more advanced blast phase CML have fewer responses of shorter duration in comparison to patients with chronic phase disease. Given these limitations associated with STI571, other inhibitors of p210bcr/abl may be useful in a clinical setting. Tyrphostins are a class of inhibitors that mimic the polypeptide substrates of BCR-ABL and are noncompetitive with respect to ATP (unlike STI571). In vitro studies with the tyrphostin, NSC680410, show that it causes down-regulation of p210bcr/abl protein levels and induces apoptosis via a mitochondrial pathway. Preliminary results indicate that NSC680410 and STI571 activate distinct signaling pathways. Elucidation of these pathways will reveal opportunities to improve the efficacy of the tyrosine kinase inhibitors.