ArticleEuropean journal of medicinal chemistry2018
Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK).
Article in European journal of medicinal chemistry, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
105 citing papers in PubMed, 1 synthesis or guideline pooled it, 215 citations in OpenAlex.
- EML4-ALK in Non-small Cell Lung Cancer: Molecular Mechanisms and Targeted Therapies.Technology in cancer research & treatmentPooled it
- Article
- Three decades of anaplastic lymphoma kinase: from physiological roles to cancer and immune evasion.Cancer metastasis reviews · 2026Review
- C-MET tyrosine kinase receptor: mechanisms, clinical applications and future perspectives in cancer therapy.Signal transduction and targeted therapy · 2026Review
- Proteolysis Targeting Chimeric-Based Technology in Myeloma and Lymphoma.Molecular cancer therapeutics · 2026Review
- PAX3::FOXO1-Targeting PROTAC Induces Myogenic Differentiation of Fusion-Positive Rhabdomyosarcoma Cells.Cancers · 2026Article
- Review
- ALK rearrangements and resistance mutations in non-small cell lung cancer: molecular mechanisms and therapeutic implications.Cancer chemotherapy and pharmacology · 2026Review
- Review
- Prospects and advances of PROTAC in the treatment of hematologic malignancies.Experimental hematology & oncology · 2026Review
- Induced proximity-based therapeutic modalities.Nature reviews. Drug discovery · 2026Review
- PROTAC-based protein degradation: a window of opportunity for melanoma therapy.Journal of biomedical science · 2026Review
- Article
- Leveraging Targeted Protein Degradation for G Protein-Coupled Receptors: The Development of CCR2 Molecular Degraders.Journal of medicinal chemistry · 2025Article
- FDA-approved kinase inhibitors in PROTAC design, development and synthesis.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- PROTAC Enabling FormulationMolecular pharmaceutics · 2025Article
- Targeted Degradation of Class 1 HDACs With PROTACs is Highly Effective at Inducing DLBCL Cell Death.EJHaem · 2025Article
- Synthesis, biological evaluation and clinical trials of Cereblon-based PROTACs.Communications chemistry · 2025Review
- ALK in cancer: from function to therapeutic targeting.Nature reviews. Cancer · 2025Review
45 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non-small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU-DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5-8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.