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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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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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