ArticleProceedings of the National Academy of Sciences of the United States of America2021
Inhibitors of cullin-RING E3 ubiquitin ligase 4 with antitumor potential.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 23 citations in OpenAlex.
- Integrative multi-omics reveals CUL4B as a modulator of macrophage pyroptosis and innate defense againstScience advances · 2026Article
- PRAME promotes invasion and metastasis of salivary adenoid cystic carcinoma by regulating RARα stability via the cullin2 ubiquitin-proteasome system.Clinical and translational medicine · 2026Article
- E3 ubiquitin ligases orchestrate chemo-resistance in gastrointestinal malignancies: from DNA damage response to therapeutic targeting.Frontiers in oncology · 2026Review
- Cul5: immune cell function and therapeutic potential.Frontiers in immunology · 2026Review
- CRL4International journal of biological sciences · 2026Article
- Ubiquitination of transcription factors in cancer: unveiling therapeutic potential.Molecular oncology · 2025Review
- Cullin-RING Ubiquitin Ligases in Neurodevelopment and Neurodevelopmental Disorders.Biomedicines · 2025Review
- Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer.Clinical and translational medicine · 2025Article
- CRL3Nature communications · 2024Article
- Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting.Molecular cell · 2024Article
- CRL4b Inhibition Ameliorates Experimental Autoimmune Encephalomyelitis Progression.Journal of immunology (Baltimore, Md. : 1950) · 2024Article
- Personalized drug screening in patient-derived organoids of biliary tract cancer and its clinical application.Cell reports. Medicine · 2023Article
- Somatic gain-of-function mutations in BUD13 promote oncogenesis by disrupting Fbw7 function.The Journal of experimental medicine · 2023Article
- Review
- The NF-κB Pharmacopeia: Novel Strategies to Subdue an Intractable Target.Biomedicines · 2022Review
- [6]-Paradol suppresses proliferation and metastases of pancreatic cancer by decreasing EGFR and inactivating PI3K/AKT signaling.Cancer cell international · 2021Article
- Targeting Cullin-RING E3 Ubiquitin Ligase 4 by Small Molecule Modulators.Journal of cellular signaling · 2021Article
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
Cullin-RING (really intersting new gene) E3 ubiquitin ligases (CRLs) are the largest E3 family and direct numerous protein substrates for proteasomal degradation, thereby impacting a myriad of physiological and pathological processes including cancer. To date, there are no reported small-molecule inhibitors of the catalytic activity of CRLs. Here, we describe high-throughput screening and medicinal chemistry optimization efforts that led to the identification of two compounds, 33-11 and KH-4-43, which inhibit E3 CRL4 and exhibit antitumor potential. These compounds bind to CRL4's core catalytic complex, inhibit CRL4-mediated ubiquitination, and cause stabilization of CRL4's substrate CDT1 in cells. Treatment with 33-11 or KH-4-43 in a panel of 36 tumor cell lines revealed cytotoxicity. The antitumor activity was validated by the ability of the compounds to suppress the growth of human tumor xenografts in mice. Mechanistically, the compounds' cytotoxicity was linked to aberrant accumulation of CDT1 that is known to trigger apoptosis. Moreover, a subset of tumor cells was found to express cullin4 proteins at levels as much as 70-fold lower than those in other tumor lines. The low-cullin4-expressing tumor cells appeared to exhibit increased sensitivity to 33-11/KH-4-43, raising a provocative hypothesis for the role of low E3 abundance as a cancer vulnerability.
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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.