Anaplastic lymphoma kinase (ALK) belongs to the family of receptor tyrosine kinases. Recently, the incidence of anaplastic large cell lymphoma (ALCL) with ALK rearrangement has raised considerably. The application of ALK-targeted inhibitors such as ceritinib provides an effective therapy for the treatment of ALK-positive cancers. However, with the prolongation of treatment time, the emergence of resistance is inevitable. We found that 1-(4-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-3-methoxyphenyl)-3-(2-(dimethylamino)ethyl)imidazolidin-2-one (ZX-42), a novel ceritinib derivative, could inhibit the proliferation of ALK-positive ALCL cells, induce the apoptosis of Karpas299 cells through the mitochondrial pathway in a caspase-dependent manner. In addition, ZX-42 could suppress ALK and downstream pathways including PI3K/Akt, Erk and JAK3/STAT3 and reduce the nuclear translocation of NFκB by inhibiting TRAF2/IKK/IκB pathway. Taken together, our findings indicate that ZX-42 shows more effective activity than ceritinib against ALK-positive ALCL. We hope this study can provide a direction for the structural modification of ceritinib and lay the foundation for the further development of clinical research in ALK-positive ALCL.

间变性淋巴瘤激酶 (ALK) 属于受体酪氨酸激酶家族。最近，伴有 ALK 重排的间变性大细胞淋巴瘤 (ALCL) 的发病率显着上升。色瑞替尼等 ALK 靶向抑制剂的应用为治疗 ALK 阳性癌症提供了有效的治疗方法。但随着治疗时间的延长，耐药性的出现在所难免。我们发现1-(4-((5-氯-4-((2-(异丙基磺酰基)苯基)氨基)嘧啶-2-基)氨基)-3-甲氧基苯基)-3-(2-(二甲基氨基)乙基)imidazolidin-2-one (ZX-42)是一种新型色瑞替尼衍生物，可抑制ALK阳性ALCL细胞增殖，通过线粒体途径以caspase依赖性方式诱导Karpas299细胞凋亡。此外，ZX-42可以抑制ALK和下游通路包括PI3K/Akt、Erk和JAK3/STAT3，并通过抑制TRAF2/IKK/IκB通路减少NFκB的核转位。总之，我们的研究结果表明 ZX-42 对 ALK 阳性 ALCL 显示出比色瑞替尼更有效的活性。希望本研究能够为色瑞替尼的结构修饰提供方向，为进一步开展ALK阳性ALCL的临床研究奠定基础。