Allosteric Inhibition of Ubiquitin-like Modifications by a Class of Inhibitor of SUMO-Activating Enzyme
Open accessAbstract
Ubiquitin-like (Ubl) post-translational modifications are potential targets for therapeutics. However, the only known mechanism for inhibiting a Ubl-activating enzyme is through targeting its ATP-binding site. Here we identify an allosteric inhibitory site in the small ubiquitin-like modifier (SUMO)-activating enzyme (E1). This site was unexpected because both it and analogous sites are deeply buried in all previously solved structures of E1s of ubiquitin-like modifiers (Ubl). The inhibitor not only suppresses SUMO E1 activity, but also enhances its degradation in vivo, presumably due to a conformational change induced by the compound. In addition, the lead compound increased the expression of miR-34b and reduced c-Myc levels in lymphoma and colorectal cancer cell lines and a colorectal cancer xenograft mouse model. Identification of this first-in-class inhibitor of SUMO E1 is a major advance in modulating Ubl modifications for therapeutic aims.
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COH000 has notable anticancer activity in vitro in colorectal cancer cells and in vivo in mouse and patient-derived xenograft models.
“Most importantly, COH000 has notable anticancer in vitro colorectal cancer cells and in vivo mouse and patient-derived xenograft models [94].”
From The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020) · cites this paper as [94]
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References 48 · Cited by 50
Research works printed but not linked: 2
- Hay RT (2005). SUMO: a history of modification. Molecular cell 18, 1– 12. 15808504
- Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, Skinner SO, Xu Q, Li MZ, Hartman ZC, (2012). A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science 335, 348– 353. 22157079 PMC4059214
- Authors
- Li, Y.-J., Du, L., Wang, J., Vega, R., Lee, T. D., Miao, Y., Aldana-Masangkay, G., Samuels, E. R., Li, B., Ouyang, S. X., Colayco, S. A., Bobkova, E. V., Divlianska, D. B., Sergienko, E., Chung, T. D. Y., Fakih, M., & Chen, Y.
- Affiliations
- City Of Hope National Medical Center (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Chen, Yuan
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 26
- Issue
- 2
- Pages
- 278-288.e6
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC6524651
- OpenAlex
- W2906239583
- Cited by
- 50
- References
- 48
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 3 · 2023: 6 · 2022: 6 · 2021: 10 · 2020: 13 · 2019: 2 · 2018: 1
- FWCI
- 2.31
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (R01GM086171, R01GM102538, R01CA212119, R01CA216987, R03DA026556, R44CA189499, U54 HG005033)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Keywords
- allosteric inhibition, E1, ubiquitin-like modification, SUMO, allosteric site, protein degradation, miR-34b, c-Myc, lymphoma, colorectal cancer, xenograft mouse model
- MeSH terms
- Allosteric Regulation, Allosteric Site, Animals, Humans, Transplantation, Heterologous, Proto-Oncogene Proteins c-myc, Mice, SCID, Ubiquitin, MicroRNAs, Ubiquitin-Activating Enzymes, Cell Line, Tumor, Mice, Small Molecule Libraries, Ubiquitination, High-Throughput Screening Assays, Sumoylation
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