Harmonizing the craft of crafting clinically endorsed small-molecule BCR-ABL tyrosine kinase inhibitors for the treatment of hematological malignancies

作者：Lu Sun, Pengcheng Yang, Luan Li, Jinfeng Sun, Yatao Wang · 发表于：European Journal of Pharmaceutical Sciences · 年份：2023 · DOI：10.1016/j.ejps.2023.106678 · 被引用次数：9 · 研究领域：Chronic Myeloid Leukemia Treatments、Quinazolinone synthesis and applications、Chronic Lymphocytic Leukemia Research

The advancement and practical use of small-molecule tyrosine kinase inhibitors (TKIs) that specifically target the BCR-ABL fusion protein have introduced a revolutionary era of precision medicine for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). This review offers a comprehensive exploration of the synthesis, mechanisms of action, and clinical implementation of clinically validated TKIs in the context of BCR-ABL, emphasizing the remarkable strides made in achieving therapeutic precision. We delve into the intricate design and synthesis of these small molecules, highlighting the synthetic strategies and modifications that have led to increased selectivity, enhanced binding affinities, and reduced off-target effects. Additionally, we discuss the structural biology of BCR-ABL inhibition and how it informs drug design. The success of these compounds in inhibiting aberrant kinase activity is a testament to the meticulous refinement of the synthetic process. Furthermore, this review provides a detailed analysis of the clinical applications of these TKIs, covering not only their efficacy in achieving deep molecular responses but also their impact on patient outcomes, safety profiles, and resistance mechanisms. We explore ongoing research efforts to overcome resistance and enhance the therapeutic potential of these agents. In conclusion, the synthesis and utilization of clinically validated small-molecule ...