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Updated: Nov 21, 2025
Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
Published on: May 15, 2019
Discovery of a PROTAC targeting ALK with in vivo activity
Guoyi Yan1, Xinxin Zhong2, Lin Yue2
1State 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.
Abstract:
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.
Insights
Researchers developed novel anaplastic lymphoma kinase (ALK) degraders using proteolysis targeting chimeras (PROTACs) to overcome drug resistance. Compound B3 demonstrated potent ALK inhibition and anticancer activity, showing promise for further investigation.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Anaplastic lymphoma kinase (ALK) plays a role in various cancers.
- Drug resistance to existing ALK inhibitors limits their clinical use.
- Proteolysis targeting chimeras (PROTACs) offer a potential strategy to overcome resistance.
Purpose of the Study:
- To design and synthesize novel ALK degraders.
- To evaluate the efficacy of these degraders against ALK-driven cancers.
- To investigate a new therapeutic approach for overcoming ALK inhibitor resistance.
Main Methods:
- Conjugation of LDK378 (an ALK inhibitor) with CRBN E3 ubiquitin ligase ligands to create PROTACs.
- Synthesis of a series of ALK degraders.
- In vitro evaluation of compound B3 in H3122 cell line for ALK inhibition and antiproliferative effects.
- In vivo assessment of antiproliferative activity in a xenograft tumor model.
Main Results:
- Compound B3 exhibited potent and selective inhibition of ALK.
- B3 effectively reduced cellular levels of ALK fusion proteins in a concentration- and time-dependent manner.
- B3 demonstrated improved in vitro anticancer activity compared to LDK378.
- Acceptable antiproliferative activity was observed in a xenograft tumor model.
Conclusions:
- The designed ALK degraders, particularly compound B3, show significant potential.
- Compound B3 possesses in vitro and in vivo anticancer activities.
- ALK degrader B3 warrants further investigation as a therapeutic agent for ALK-driven cancers.
