BCR-ABL激酶抑制剂的研究进展

Advance Research of BCR-ABL Kinase Inhibitor

关键词:  慢性粒细胞白血病  BCR-ABL  抑制剂  选择性

Key words:  chronic granulocytic leukemia  BCR-ABL  inhibitor  selectivity

摘要:

慢性粒细胞白血病(chronic myelogenous leukemia，CML)是自我更新的造血干细胞恶性骨髓增生性疾病，约90%的患者外周血细胞中可以检测到一种异常染色体——PH染色体。9号染色体的BCR基因与22号染色体的c-ABL基因形成了新的基因序列——BCR-ABL融合基因。该基因编码的P210蛋白质增强了酪氨酸激酶的活性，从而产生了细胞凋亡的抑制作用，这与慢性粒细胞白血病的发生有着密切关联。第一个小分子靶向抗肿瘤药物是伊马替尼(imatinib)，它可以有效抑制BCR-ABL激酶。然而随着不同种类的突变型BCR-ABL激酶的出现，伊马替尼却无可奈何。第二代BCR-ABL激酶抑制剂主要针对伊马替尼耐药的突变型BCR-ABL，并同时出现了作用于多靶点的治疗慢性粒细胞白血病的抑制剂，但这些都无法对T315I突变型BCR-ABL激酶起效。第三代BCR-ABL激酶抑制剂主要针对T315I突变型BCR-ABL激酶，包括单独抑制以及与其他药物协同作用，同时也正在尝试提高药物的选择性，减少不良反应的发生。BCR-ABL激酶抑制剂经历了由单靶点到多靶点的发展历程，在攻克野生型及突变型BCR-ABL激酶各个治疗难题的同时，正向着高选择性高有效性的方向不断发展。

Abstract:

Chronic myelogenous leukemia(CML) is a type of self-renewal stem cells malignant myeloproliferative disease. PH chromosome which is an abnormal chromosome can be detected in about 90% patients with peripheral blood. Part of BCR gene from chromosome 22 is fused with the ABL gene on chromosome 9, resulting in formation of BCR-ABL fusion gene, a new gene sequence. The protein p210 which is encoded by this abnormal fusion gene could enhance the activity of tyrosine kinase, resulting in the inhibition of apoptosis. The action of the BCR-ABL protein is the pathophysiologic cause of chronic myelogenous leukemia. Imatinib is the first approved drug of BCR-ABL kinase inhibitor. However, multiple drug resistance of tumor cells against imatinib has emerged due to the mutations in the BCR-ABL kinases. To overcome imatinib resistance, the second generation BCR-ABL inhibitors were developed, including multi-target kinase inhibitors. Although these inhibitors have been proved to be effective against most mutations of BCE-ABL except T3151. Subsequently, the third generation BCR-ABL kinase inhibitors targeting T3151 mutation have been developed. These inhibitors could be used as single agent or combined with other drugs. Some efforts have been performed to increase the inhibitor selective and reduce adverse side effects. With developing from the single target to multi targets, BCR-ABL inhibitors could inhibit wild type and mutanted BCR-ABL kinases. The recent progress in research on high selectivity and more potent BCR-ABL inhibitors is ongoing.