崔文禹, 赵若熙, 韩路路, 倪伟伟, 李飞, 韩进松. 新型BCR-ABL激酶抑制剂的研究进展J. 药学学报, 2023, 58(2): 258-273. DOI: 10.16438/j.0513-4870.2022-0807
引用本文: 崔文禹, 赵若熙, 韩路路, 倪伟伟, 李飞, 韩进松. 新型BCR-ABL激酶抑制剂的研究进展J. 药学学报, 2023, 58(2): 258-273. DOI: 10.16438/j.0513-4870.2022-0807
CUI Wen-yu, ZHAO Ruo-xi, HAN Lu-lu, NI Wei-wei, LI Fei, HAN Jin-song. Advances in the study of new BCR-ABL kinase inhibitorsJ. Acta Pharmaceutica Sinica, 2023, 58(2): 258-273. DOI: 10.16438/j.0513-4870.2022-0807
Citation: CUI Wen-yu, ZHAO Ruo-xi, HAN Lu-lu, NI Wei-wei, LI Fei, HAN Jin-song. Advances in the study of new BCR-ABL kinase inhibitorsJ. Acta Pharmaceutica Sinica, 2023, 58(2): 258-273. DOI: 10.16438/j.0513-4870.2022-0807

新型BCR-ABL激酶抑制剂的研究进展

Advances in the study of new BCR-ABL kinase inhibitors

  • 摘要: 融合基因BCR-ABL在人体内表达的蛋白质是一种异常的酪氨酸激酶, 可导致慢性髓系白血病(chronic myeloid leukemia, CML)。随着对CML发病机制的进一步研究, 人们发现开发选择性抑制异常BCR-ABL酪氨酸激酶的化合物是值得关注的研究方向。前三代BCR-ABL抑制剂为正构抑制剂, 该抑制剂竞争性阻断ABL蛋白酪氨酸激酶与ATP的结合, 阻止其激活下游信号。第四代BCR-ABL抑制剂通过与肉豆蔻酰口袋结合, 变构抑制ABL蛋白酪氨酸激酶, 具有更强的选择性且保持对耐药性突变蛋白的活性。蛋白水解靶向嵌合(proteolytic targeting chimera, PROTAC)、共价抑制剂和双重靶向抑制剂等新型药物设计策略也为BCR-ABL激酶抑制剂的开发提供了新的方向。本文综述了近年来有关BCR-ABL激酶抑制剂的研究进展, 并讨论了各种新型BCR-ABL抑制剂的药物设计策略。

     

    Abstract: The oncogenic product of BCR-ABL is an abnormal tyrosine kinase that causes chronic myeloid leukemia (CML). With further research into the pathogenesis of CML, the discovery of compounds that selectively inhibit abnormal BCR-ABL tyrosine kinases is a research focus worthy of attention. The first three generations of BCR-ABL inhibitors are orthosteric inhibitors, which competitively block the binding of ABL protein tyrosine kinase to ATP and prevent it from activating downstream signals. The fourth-generation BCR-ABL inhibitors allosterically inhibit ABL protein tyrosine kinase by binding to the myristoyl pocket, providing greater selectivity and maintaining activity against drug-resistant mutations proteins. Novel drug design strategies such as proteolytic targeting chimera (PROTAC), covalent inhibitors and dual targeting inhibitors also provide new directions for the development of BCR-ABL kinase inhibitors. This paper reviews recent research advances on BCR-ABL kinase inhibitors and discusses drug design strategies for various novel BCR-ABL inhibitors.

     

/

返回文章
返回