EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in cancer targeted therapy.

EML4-ALK和NPM-ALK融合蛋白具有组成性激活的ALK（间变性淋巴瘤激酶）活性，进而导致非小细胞肺癌和间变性大细胞淋巴瘤（ALCL）的发展。FDA批准的ALK抑制剂药物可导致明显的癌症消退。但是，最终会出现耐药性，成为临床上的一大障碍。靶向嵌合体的新型蛋白水解（PROTAC）技术平台为耐药性提供了潜在的治疗策略。在本文中，我们设计并合成了一系列基于Brigatinib和VHL-1的ALK PROTAC，并筛选了SIAIS117作为最佳降解剂，该降解剂不仅阻断SR和H2228癌细胞的生长，而且降解ALK蛋白。此外，SIAIS117在外源表达G1202R抗性ALK蛋白的293T细胞系中也显示出比Brigatinib更好的生长抑制效果。此外，它还降解了G1202R突变型ALK蛋白体外。最后，它具有潜在的抗小细胞肺癌增殖能力。因此，我们成功地产生了可以在癌症靶向治疗中克服耐药性的降解剂SIAIS117。