ArticleJournal of medicinal chemistry2023
Catalytic Degraders Effectively Address Kinase Site Mutations in EML4-ALK Oncogenic Fusions.
Article in Journal of medicinal chemistry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it.
- EML4-ALK in Non-small Cell Lung Cancer: Molecular Mechanisms and Targeted Therapies.Technology in cancer research & treatmentPooled it
- Article
- Safety considerations for cereblon-recruiting targeted protein degraders.Nature reviews. Drug discovery · 2026Review
- Property-Based Optimization of Cereblon-Based Molecular Glue Degraders.ACS medicinal chemistry letters · 2025Review
- Targeted protein degradation for cancer therapy.Nature reviews. Cancer · 2025Review
- Advancing Design Strategy of PROTACs for Cancer Therapy.MedComm · 2025Review
- ALK in cancer: from function to therapeutic targeting.Nature reviews. Cancer · 2025Review
- Targeted protein degradation: advances in drug discovery and clinical practice.Signal transduction and targeted therapy · 2024Review
- Discovery of ZLC491 as a Potent, Selective, and Orally Bioavailable CDK12/13 PROTAC Degrader.Journal of medicinal chemistry · 2024Article
- Characteristic roadmap of linker governs the rational design of PROTACs.Acta pharmaceutica Sinica. B · 2024Review
- Targeted protein degradation: from mechanisms to clinic.Nature reviews. Molecular cell biology · 2024Review
- Targeting fusion oncoproteins in childhood cancers: challenges and future opportunities for developing therapeutics.Journal of the National Cancer Institute · 2024Article
- Development of sulfonyl fluoride chemical probes to advance the discovery of cereblon modulators.RSC medicinal chemistry · 2024Article
- A small-molecule degrader selectively inhibits the growth ofiScience · 2024Article
- Selective and Potent PROTAC Degraders of c-Src Kinase.ACS chemical biology · 2024Article
- ALK inhibitors in cancer: mechanisms of resistance and therapeutic management strategies.Cancer drug resistance (Alhambra, Calif.) · 2024Review
- Development of a covalent cereblon-based PROTAC employing a fluorosulfate warhead.RSC chemical biology · 2023Article
- Targeted degradation of extracellular secreted and membrane proteins.Trends in pharmacological sciences · 2023Review
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
Heterobifunctional degraders, known as proteolysis targeting chimeras (PROTACs), theoretically possess a catalytic mode-of-action, yet few studies have either confirmed or exploited this potential advantage of event-driven pharmacology. Degraders of oncogenic EML4-ALK fusions were developed by conjugating ALK inhibitors to cereblon ligands. Simultaneous optimization of pharmacology and compound properties using ternary complex modeling and physicochemical considerations yielded multiple catalytic degraders that were more resilient to clinically relevant ATP-binding site mutations than kinase inhibitor drugs. Our strategy culminated in the design of the orally bioavailable derivative CPD-1224 that avoided hemolysis (a feature of detergent-like PROTACs), degraded the otherwise recalcitrant mutant L1196M/G1202R in vivo, and commensurately slowed tumor growth, while the third generation ALK inhibitor drug lorlatinib had no effect. These results validate our original therapeutic hypothesis by exemplifying opportunities for catalytic degraders to proactively address binding site resistant mutations in cancer.
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