Mechanism of action of a novel tyrosine kinase inhibitor

新型酪氨酸激酶抑制剂的作用机制

• 批准号: 6522876
• 负责人: Joya Chandra
• 金额: $ 4.62万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-17 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6522876
• 关键词: antineoplastics; apoptosis; chronic myelogenous leukemia; cytochrome c; enzyme inhibitors; human tissue; immunocytochemistry; myeloid stem cell; neoplasm /cancer pharmacology; protein tyrosine kinase; superoxide dismutase; western blottings

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.

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，这是一种疾病，其中鉴定分子缺陷促进了新的治疗策略。在95％的CML病例中，来自9号染色体的C-ABL基因与22号染色体上的BCR基因易位和融合，从而引起P210BCR/ABL蛋白酪氨酸酪氨酸激酶。 P210BCR/ABL激酶活性的抑制代表了药理目标。 STI571是将这些酪氨酸激酶抑制剂引入诊所中的第一个。但是，STI571的持续临床评估表明，该药物的最佳功效需要连续给药。此外，初步报告表明，与慢性期疾病患者相比，持续时间更短的持续时间的反应较短。鉴于与STI571相关的这些局限性，P210BCR/ABL的其他抑制剂在临床环境中可能很有用。泰腹蛋白是模仿BCR-ABL多肽底物的一类抑制剂，相对于ATP不竞争（与STI571不同）。对Tyrphostin，NSC680410的体外研究表明，它会导致P210BCR/ABL蛋白水平的下调，并通过线粒体途径诱导凋亡。初步结果表明NSC680410和STI571激活不同的信号通路。阐明这些途径将揭示机会提高酪氨酸激酶抑制剂的功效。