The DOI matches its Crossref record; 35 of the 35 references it cites were found in a registry or an index.
Discovery of a Functional Covalent Ligand Targeting an Intrinsically Disordered Cysteine within MYC
Open accessAbstract
MYC is a major oncogenic transcriptional driver of most human cancers that has remained intractable to direct targeting because much of MYC is intrinsically disordered. Here, we have performed a cysteine-reactive covalent ligand screen to identify compounds that could disrupt the binding of MYC to its DNA consensus sequence in vitro and also impair MYC transcriptional activity in situ in cells. We have identified a covalent ligand, EN4, that targets cysteine 171 of MYC within a predicted intrinsically disordered region of the protein. We show that EN4 directly targets MYC in cells, reduces MYC and MAX thermal stability, inhibits MYC transcriptional activity, downregulates multiple MYC transcriptional targets, and impairs tumorigenesis. We also show initial structure-activity relationships of EN4 and identify compounds that show improved potency. Overall, we identify a unique ligandable site within an intrinsically disordered region of MYC that leads to inhibition of MYC transcriptional activity.
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“ABPP was paired with a MYC transcription factor activity assay to identify a covalent MYC ligand, EN4 (ref.179).”
From Advances in covalent drug discovery (2022) · cites this paper as [179]
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Cites
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Schneider, C. A., Rasband, W. S., & Eliceiri, K. W. (2012) · Nature Methods · doi:10.1038/nmeth.2089 · Cited by 64,638
Salmon provides fast and bias-aware quantification of transcript expression
Patro, R., Duggal, G., Love, M. I., Irizarry, R. A., & Kingsford, C. (2017) · Nature Methods · doi:10.1038/nmeth.4197 · Cited by 12,700
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Monitoring Drug Target Engagement in Cells and Tissues Using the Cellular Thermal Shift Assay
Molina, D. M., Jafari, R., Ignatushchenko, M., Seki, T., Larsson, E. A., Dan, C., Sreekumar, L., Cao, Y., & Nordlund, P. (2013) · Science · doi:10.1126/science.1233606 · Cited by 2,261
Quantitative reactivity profiling predicts functional cysteines in proteomes
Weerapana, E., Wang, C., Simon, G. M., Richter, F., Khare, S., Dillon, M. B. D., Bachovchin, D. A., Mowen, K., Baker, D., & Cravatt, B. F. (2010) · Nature · doi:10.1038/nature09472 · Cited by 1,684
Reflecting on 25 years with MYC
Meyer, N., & Penn, L. Z. (2008) · Nature Reviews Cancer · doi:10.1038/nrc2231 · Cited by 1,575
Proteome-wide covalent ligand discovery in native biological systems
Backus, K. M., Correia, B. E., Lum, K. M., Forli, S., Horning, B. D., González-Páez, G. E., Chatterjee, S., Lanning, B. R., Teijaro, J. R., Olson, A. J., et al. (2016) · Nature · doi:10.1038/nature18002 · Cited by 940
Drugging the ‘undruggable’ cancer targets
Dang, C. V., Reddy, E. P., Shokat, K. M., & Soucek, L. (2017) · Nature Reviews Cancer · doi:10.1038/nrc.2017.36 · Cited by 927
Targeting oncogenic Myc as a strategy for cancer treatment
Chen, H., Liu, H., & Qing, G. (2018) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-018-0008-7 · Cited by 834
MYC: Connecting selective transcriptional control to global RNA production
Kress, T. R., Sabò, A., & Amati, B. (2015) · Nature reviews. Cancer · doi:10.1038/nrc3984 · Cited by 521
Cited by
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The MYC oncogene — the grand orchestrator of cancer growth and immune evasion
Dhanasekaran, R., Deutzmann, A., Mahauad‐Fernandez, W. D., Hansen, A. S., Gouw, A. M., & Felsher, D. W. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00549-2 · Cited by 1,044
Advances in covalent drug discovery
Boike, L., Henning, N. J., & Nomura, D. K. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00542-z · Cited by 823
Self-citationAdvances in Targeting ‘Undruggable’ transcription Factors With Small Molecules
Henley, M. J., & Koehler, A. N. (2021) · Nature Reviews Drug Discovery · doi:10.1038/s41573-021-00199-0 · Cited by 409
Modulating biomolecular condensates: a novel approach to drug discovery
Mitrea, D. M., Mittasch, M., Gomes, B. F., Klein, I. A., & Murcko, M. A. (2022) · Nature Reviews Drug Discovery · doi:10.1038/s41573-022-00505-4 · Cited by 434
Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc
Madden, S. K., de Araujo, A. D., Gerhardt, M., Fairlie, D. P., & Mason, J. M. (2021) · Molecular Cancer · doi:10.1186/s12943-020-01291-6 · Cited by 404
Metadata
- Authors
- Boike, L., Cioffi, A. G., Majewski, F. C., Co, J., Henning, N. J., Jones, M. D., Liu, G., McKenna, J. M., Tallarico, J. A., Schirle, M., & Nomura, D. K.
- Affiliations
- University of California, Berkeley (US)
- Innovative Genomics Institute (US)
- Corresponding author
- Nomura, Daniel K.
- ORCID
- Venue
- Cell Chemical Biology
- Publisher
- Elsevier BV
- Published
- 2021-01
- Volume
- 28
- Issue
- 1
- Pages
- 4-13.e17
- ISSN
- 2451-9448 (ISSN-L)
- 2451-9456
- PMC
- PMC7854864
- OpenAlex
- W3089235055
- Cited by
- 154
- References
- 35
- Citations by year
- 2026: 25 · 2025: 39 · 2024: 29 · 2023: 17 · 2022: 20 · 2021: 22
- FWCI
- 4.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell chemical biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- Mark Foundation For Cancer Research
- Novartis Institutes for BioMedical Research
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Physical Sciences › Chemistry › Organic Chemistry › Click Chemistry and Applications
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- c-Myc, intrinsically disordered proteins, covalent ligands, protein thermal stability, structure-activity relationship, MYC inhibitors, carcinogenesis
- MeSH terms
- Cells, Cultured, Cysteine, Dose-Response Relationship, Drug, Humans, Ligands, Molecular Structure, Proto-Oncogene Proteins c-myc
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