Irgit Ayca, Kamıs Reyhan, Sever Belgin, Tuyun Amaç Fatih, Otsuka Masami, Fujita Mikako, Demirci Hasan, Ciftci Halilibrahim
Department of Molecular Biology and Genetics, Koc University, Istanbul, Turkey.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Anadolu University, Eskisehir, Turkey.
Arch Pharm (Weinheim). 2025 May;358(5):e70005. doi: 10.1002/ardp.70005.
Abelson (ABL1) tyrosine kinase is an essential component of non-receptor tyrosine kinases and is associated with numerous cellular processes, including differentiation and proliferation. The structural features of ABL1 include a distinct N-terminal cap region, a C-terminal tail, a bilobed kinase, SH2, and SH3 domains. These domains enable its engagement in several signaling cascades and dynamic control. The pathophysiology of chronic myeloid leukemia (CML) is mainly driven by the BCR-ABL1 oncoprotein, arising from dysregulation of ABL1 kinase, namely through its fusion to the breakpoint cluster region (BCR) gene. ABL1 is a crucial target in the treatment of CML as the BCR-ABL1 fusion causes uncontrolled cellular proliferation and resistance to apoptosis. Tyrosine kinase inhibitors (TKIs) targeting the ABL1 tyrosine kinase are playing a critical role in the treatment of CML through the inhibition of persistently activated signaling pathways mediated by the BCR-ABL1 fusion protein. The article examines the structural characteristics of ABL1, how they relate to CML, and the interactions between ABL1 and the current FDA-approved TKIs, emphasizing the kinase's critical function in carcinogenesis and its possible target status for tyrosine kinase inhibitors.
阿贝尔森（ABL1）酪氨酸激酶是非受体酪氨酸激酶的重要组成部分，与包括分化和增殖在内的众多细胞过程相关。ABL1的结构特征包括一个独特的N端帽状区域、一个C端尾巴、一个双叶激酶、SH2和SH3结构域。这些结构域使其能够参与多个信号级联反应和动态调控。慢性髓性白血病（CML）的病理生理学主要由BCR-ABL1癌蛋白驱动，该蛋白源于ABL1激酶的失调，即通过其与断裂点簇集区域（BCR）基因的融合产生。ABL1是CML治疗中的关键靶点，因为BCR-ABL1融合导致细胞不受控制地增殖并产生凋亡抗性。靶向ABL1酪氨酸激酶的酪氨酸激酶抑制剂（TKIs）通过抑制由BCR-ABL1融合蛋白介导的持续激活的信号通路，在CML治疗中发挥着关键作用。本文研究了ABL1的结构特征、它们与CML的关系以及ABL1与目前美国食品药品监督管理局（FDA）批准的TKIs之间的相互作用，强调了该激酶在致癌过程中的关键作用及其作为酪氨酸激酶抑制剂可能的靶点地位。
