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.

慢性粒细胞白血病 (CML) 是最常见的骨髓增殖性疾病，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。在超过 95% 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 激酶活性代表了一个药理学目标。 STI571是第一个引入临床的酪氨酸激酶抑制剂。然而，正在进行的 STI571 临床评估表明，需要持续给药才能发挥该药物的最佳疗效。此外，初步报告表明，与慢性期疾病患者相比，晚期急变期 CML 患者的反应较少且持续时间较短。鉴于 STI571 的这些局限性，其他 p210bcr/abl 抑制剂可能在临床环境中有用。酪氨酸磷酸化抑制剂是一类模拟 BCR-ABL 多肽底物的抑制剂，并且与 ATP 不具有竞争性（与 STI571 不同）。酪氨酸磷酸酶 NSC680410 的体外研究表明，它会导致 p210bcr/abl 蛋白水平下调，并通过线粒体途径诱导细胞凋亡。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提高酪氨酸激酶抑制剂功效的机会。