School of Pharmacy, Lanzhou University, 199 West Donggang Rd., 730000, Lanzhou, China.
Curr Med Chem. 2024;31(20):2872-2894. doi: 10.2174/0929867330666230519105900.
Chronic myeloid leukemia (CML) is a kind of malignant tumor formed by the clonal proliferation of bone marrow hematopoietic stem cells. BCR-ABL fusion protein, found in more than 90% of patients, is a vital target for discovering anti- CML drugs. Up to date, imatinib is the first BCR-ABL tyrosine kinase inhibitor (TKI) approved by the FDA for treating CML. However, the drug resistance problems appeared for many reasons, especially the T135I mutation, a "gatekeeper" of BCR-ABL. Currently, there is no long-term effective and low side effect drug in clinical.
This study intends to find novel TKIs targeting BCR-ABL with high inhibitory activity against T315I mutant protein by combining artificial intelligence technology and cell growth curve, cytotoxicity, flow cytometry and Western blot experiments.
The obtained compound was found to kill leukemia cells, which had good inhibitory efficacy in BaF3/T315I cells. Compound no 4 could induce cell cycle arrest, cause autophagy and apoptosis, and inhibit the phosphorylation of BCR-ABL tyrosine kinase, STAT5 and Crkl proteins.
The results indicated that the screened compound could be used as a lead compound for further research to discover ideal chronic myeloid leukemia therapeutic drugs.
慢性髓性白血病（CML）是一种由骨髓造血干细胞克隆性增殖形成的恶性肿瘤。在超过 90%的患者中发现的 BCR-ABL 融合蛋白是发现抗 CML 药物的重要靶标。迄今为止，伊马替尼是 FDA 批准的第一种用于治疗 CML 的 BCR-ABL 酪氨酸激酶抑制剂（TKI）。然而，由于多种原因，出现了耐药问题，尤其是 BCR-ABL 的“守门员”T135I 突变。目前，临床上还没有长期有效、低副作用的药物。
本研究旨在通过结合人工智能技术和细胞生长曲线、细胞毒性、流式细胞术和 Western blot 实验，寻找对 T315I 突变蛋白具有高抑制活性的新型 BCR-ABL 靶向 TKI。
发现获得的化合物能够杀伤白血病细胞，对 BaF3/T315I 细胞具有良好的抑制效果。化合物 4 能够诱导细胞周期停滞，引起自噬和凋亡，并抑制 BCR-ABL 酪氨酸激酶、STAT5 和 Crkl 蛋白的磷酸化。
结果表明，筛选出的化合物可作为进一步研究的先导化合物，以发现理想的慢性髓性白血病治疗药物。
