慢性粒细胞白血病（CML）是由BCR-ABL融合蛋白引起的恶性血液肿瘤，该融合蛋白与ATP结合发挥酪氨酸酶活性并持续激活下游磷酸化途径。以伊马替尼为代表的酪氨酸激酶抑制剂(TKI)是临床治疗CML的关键药物。而靶点突变导致严重的耐药问题，尤其是T315I突变仍然是一个尚未解决的挑战，尽管第三代TKI Ponatinib对T315I突变疗效良好，但心脏毒性限制了其临床应用。尽管如此，帕纳替尼的结构优化仍然是克服突变带来的耐药性的潜在策略。在此，我们展示了一系列新型BCR-ABL/T315I酪氨酸激酶抑制剂，这些抑制剂是通过使用我们团队之前报道的BCR-ABL/T315I抑制剂ZINC21710815作为先导化合物进行虚拟筛选，并针对T315I先导化合物进行结构优化而获得的。突变，以及通过活性评估和机制研究筛选两种新化合物，W4和W8。 W4和W8对BaF3/T315I具有更好的细胞死亡诱导作用和特殊选择性，值得进一步深入研究，以获得更理想的抗CML药物作为先导化合物。Copyright © 2024。Published by Elsevier B.V.

Chronic Myeloid Leukemia (CML) is a malignant hematologic tumor caused by BCR-ABL fusion protein that binds with ATP to exert tyrosinase activity and persistently activates downstream phosphorylation pathways. The tyrosine kinase inhibitors (TKIs) represented by Imatinib are the key clinical therapy to the CML. While the mutations on the target lead to the serious drug resistance problems, especially the T315I mutation remains an unresolved challenge, and the cardiotoxicity has limited the clinical application of the third generation TKI Ponatinib despite its favorable efficacy against the T315I mutation. Even though, structural optimization of Ponatinib remains a potential strategy to overcome the resistance imposed by the mutation. Herein, we present a series of novel BCR-ABL/T315I tyrosine kinase inhibitors obtained by virtual screening using ZINC21710815, a BCR-ABL/T315I inhibitor reported earlier by our team, as a lead compound, and structural optimization of lead compounds against the T315I mutation, as well as screening of two novel compounds by activity evaluation and mechanistic studies, W4 and W8. W4 and W8 have better cell death-inducing effects and special selectivity against BaF3/T315I, which are worthy of further in-depth study to obtain more desirable anti-CML drugs as lead compounds.Copyright © 2024. Published by Elsevier B.V.