Mechanism of action of a novel tyrosine kinase inhibitor

慢性骨髓性白血病（CML）是最常见的骨髓增生性疾病，占所有白血病的20%。值得注意的是，在这种疾病中，分子缺陷的识别促进了新的治疗策略。在95%以上的CML病例中，9号染色体上的c-ABL基因易位并与22号染色体上的BCR基因融合，产生p210bcr/abl蛋白酪氨酸激酶。抑制p210bcr/abl激酶活性是一个药理目标。STI571是第一个被引入临床的酪氨酸激酶抑制剂。然而，正在进行的STI571临床评估显示，需要持续给药才能获得最佳疗效。此外，初步报告表明，与慢性期疾病患者相比，更晚期的母细胞期CML患者的反应更少，持续时间更短。考虑到STI571相关的这些局限性，p210bcr/abl的其他抑制剂可能在临床环境中有用。Tyrphostins是一类模拟BCR-ABL多肽底物的抑制剂，与ATP不具有竞争性（与STI571不同）。tyrphostin （NSC680410）的体外研究表明，它通过线粒体途径下调p210bcr/abl蛋白水平，诱导细胞凋亡。初步结果表明，NSC680410和STI571激活不同的信号通路。这些途径的阐明将揭示改善酪氨酸激酶抑制剂功效的机会。

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.