ArticleSignal transduction and targeted therapy2022
A small molecule inhibitor of the UBE2F-CRL5 axis induces apoptosis and radiosensitization in lung cancer.
Article in Signal transduction and targeted therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it, 50 citations in OpenAlex.
- A novel regulator in cancer initiation and progression: long noncoding RNA SHNG9.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023Pooled it
- Protein neddylation as a therapeutic target: challenges and opportunities.The Journal of clinical investigation · 2026Review
- Neddylation: from regulatory mechanisms to clinical implications in cancer.Journal of advanced research · 2026Review
- Unbiased CRISPR synthetic lethal screening for genetic vulnerabilities in a succinate dehydrogenase-loss model of paraganglioma.iScience · 2026Article
- Engineered romidepsin biosynthetic pathways in Escherichia coli Nissle 1917 improve the efficacy of bacteria-mediated cancer therapy.PLoS biology · 2026Article
- Decoding neddylation in malignancies: molecular mechanisms, biological functions, therapeutic resistance, and clinical potential.Cell death & disease · 2026Review
- ATMLP Enhances Radioresistance in Non-Small Cell Lung Cancer through AKT-Mediated Lipid Droplet Accumulation.International journal of biological sciences · 2026Article
- Progression on Mechanism and Therapeutic Implications of Neddylation in Lung Cancer.Oncology research · 2026Review
- The Crosstalk Between CRL5 and APC/C E3 Ligases Regulates Metastasis and Chemosensitivity of Cancer Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- The UBE2/E2 ubiquitin-conjugating enzyme family at the interface of tumor biology and antitumor immunity: mechanisms, biomarkers, and therapeutic opportunities.Frontiers in immunology · 2026Review
- CUL5-mediated ubiquitination in cancer cell therapy: context-dependent roles, molecular networks, and emerging therapeutic avenues.Frontiers in medicine · 2026Review
- Cul5: immune cell function and therapeutic potential.Frontiers in immunology · 2026Review
- Ubiquitin-conjugating Enzymes in Cancer.International journal of biological sciences · 2026Review
- The role of neddylation in colorectal cancer and its therapeutic potential.Discover oncology · 2025Review
- Neddylation inhibition induces DNA double-strand breaks, hampering tumor growth in vivo, and promotes radiosensitivity in PAX3-FOXO1 rhabdomyosarcoma.Cell death discovery · 2025Article
- Targeting metalloptosis in tumor therapy: from molecular mechanisms to application of metal nanoparticles.Molecular cancer · 2025Review
- Decoding the ubiquitin network: molecular mechanisms and therapeutic vulnerabilities for precision radio-sensitization in cancer.Molecular cancer · 2025Review
- Protein neddylation in lung tumorigenesis: Target validation and targeted therapy.Fundamental research · 2025Review
- Collisional Cross-Section Prediction for Multiconformational Peptide Ions with IM2Deep.Analytical chemistry · 2025Article
- Deciphering the roles of neddylation modification in hepatocellular carcinoma: Molecular mechanisms and targeted therapeutics.Genes & diseases · 2025Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Protein neddylation is catalyzed by a neddylation activating enzyme (NAE, E1), an E2 conjugating enzyme, and an E3 ligase. In various types of human cancers, the neddylation pathway is abnormally activated. Our previous study validated that the neddylation E2 UBE2F is a promising therapeutic target in lung cancer. Although the NAE inhibitor MLN4924/pevonedistat is currently under clinical investigation as an anti-cancer agent, there are no small molecules available that selectively target UBE2F. Here, we report, for the first time, the discovery, via structure-based virtual screen and chemical optimization, of such a small molecule, designated as HA-9104. HA-9104 binds to UBE2F, reduces its protein levels, and consequently inhibits cullin-5 neddylation. Blockage of cullin-5 neddylation inactivates cullin-RING ligase-5 (CRL5) activity, leading to accumulation of the CRL5 substrate, NOXA, to induce apoptosis. Moreover, HA-9104 appears to form the DNA adduct via its 7-azaindole group to induce DNA damage and G2/M arrest. Biologically, HA-9104 effectively suppresses the growth and survival of lung cancer cells and confers radiosensitization in both in vitro cell culture and in vivo xenograft tumor models. In summary, we discovered a small molecule, designated HA-9104, that targets the UBE2F-CRL5 axis with anti-cancer activity alone or in combination with radiation.
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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.