State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China; Department of Hepatobiliary Pancreatic Surgery, Henan Provincial People's Hospital, Henan University, Zhengzhou, China.
State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital of Sichuan University, Chengdu, China.
Eur J Med Chem. 2021 Feb 15;212:113150. doi: 10.1016/j.ejmech.2020.113150. Epub 2021 Jan 2.
Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy. In this study, a series of ALK degraders were designed and synthesized. The degraders were developed through the conjugation of LDK378 and CRBN E3 ubiquitin ligase ligands. Among all the molecules, compound B3 showed potent selective inhibitory activity to ALK and can decrease the cellular levels of ALK fusion proteins in a concentration- and time-dependent manner in H3122 cell line. Meanwhile, B3 showed improved anticancer activity in vitro comparing with LDK378 and the antiproliferative activity to xenograft tumor model was acceptable. All the results demonstrated that ALK degrader B3 with in vitro and in vivo anti-cancer activities was valuable for further investigation.
间变性淋巴瘤激酶（ALK）参与了多种癌症类型的发展。尽管已经有几种 ALK 抑制剂被推进到临床试验阶段，但耐药性的出现限制了它们的临床应用。为了克服耐药性，蛋白水解靶向嵌合体（PROTACs）可能是一种替代策略。在这项研究中，设计并合成了一系列的 ALK 降解剂。这些降解剂是通过 LDK378 和 CRBN E3 泛素连接酶配体的连接而开发的。在所有的分子中，化合物 B3 对 ALK 表现出很强的选择性抑制活性，并能以浓度和时间依赖的方式降低 H3122 细胞系中 ALK 融合蛋白的细胞水平。同时，B3 与 LDK378 相比，在体外具有更好的抗癌活性，对异种移植肿瘤模型的增殖活性也可以接受。所有的结果表明，ALK 降解剂 B3 具有体外和体内抗癌活性，值得进一步研究。
