Although anaplastic lymphoma kinase (ALK) inhibitors have good clinical efficacy, the inevitable development of drug resistance is the most common obstacle to their clinical application. There is an urgent need to develop more effective and selective ALK inhibitors to overcome the problem of drug resistance. Here, we screened a series of ALK inhibitors and found that ZX-29 displayed potent cytotoxic activity against ALK rearrangement non-small cell lung cancer (NSCLC) NCI-H2228 cells. Then, we investigated the antitumor effects of ZX-29. We demonstrated that ZX-29 time- and dose-dependently inhibited the viability of NCI-H2228 cells, induced cell cycle arrest in the G1 phase, and then they subsequently progressed into cell death. The type of cell death induced by ZX-29 was apoptosis through endoplasmic reticulum (ER) stress. Interestingly, ZX-29 induced protective autophagy, and inhibiting autophagy could enhance the antitumor effect of ZX-29. Furthermore, ZX-29 suppressed tumor growth in a mouse xenograft model. More importantly, ZX-29 could overcome the drug resistance caused by the ALK G1202R mutation. In conclusion, we demonstrated that ZX-29 showed excellent anti-ALK rearrangement NSCLC activity in vitro and in vivo and overcame the drug resistance caused by an ALK mutation. Therefore, ZX-29 is a promising antitumor drug targeting ALK rearrangement or ALK G1202R mutation NSCLC.

中文翻译：

---

ZX-29是一种新型的ALK抑制剂，可通过ER应激在ALK重排NSCLC细胞中诱导凋亡，并克服由ALK突变引起的细胞抗性。

尽管间变性淋巴瘤激酶（ALK）抑制剂具有良好的临床疗效，但耐药性的不可避免发展是其临床应用的最常见障碍。迫切需要开发更有效和选择性的ALK抑制剂，以克服耐药性问题。在这里，我们筛选了一系列ALK抑制剂，发现ZX-29对ALK重排非小细胞肺癌（NSCLC）NCI-H2228细胞显示出有效的细胞毒活性。然后，我们研究了ZX-29的抗肿瘤作用。我们证明ZX-29在时间和剂量上均抑制NCI-H2228细胞的活力，诱导细胞周期停滞在G1期，然后它们随后发展为细胞死亡。ZX-29诱导的细胞死亡类型是通过内质网（ER）应激引起的细胞凋亡。有趣的是 ZX-29诱导保护性自噬，抑制自噬可增强ZX-29的抗肿瘤作用。此外，ZX-29在小鼠异种移植模型中抑制了肿瘤的生长。更重要的是，ZX-29可以克服由ALK G1202R突变引起的耐药性。总之，我们证明ZX-29在体外和体内均表现出优异的抗ALK重排NSCLC活性，克服了由ALK突变引起的耐药性。因此，ZX-29是靶向ALK重排或ALK G1202R突变NSCLC的有前途的抗肿瘤药物。我们证明ZX-29在体外和体内均表现出优异的抗ALK重排NSCLC活性，克服了由ALK突变引起的耐药性。因此，ZX-29是靶向ALK重排或ALK G1202R突变NSCLC的有前途的抗肿瘤药物。我们证明ZX-29在体外和体内均表现出优异的抗ALK重排NSCLC活性，克服了由ALK突变引起的耐药性。因此，ZX-29是靶向ALK重排或ALK G1202R突变NSCLC的有前途的抗肿瘤药物。