The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy
Open accessAbstract
Intrinsic and acquired drug resistance and induction of secondary malignancies limit successful chemotherapy. Because mutagenic translesion synthesis (TLS) contributes to chemoresistance as well as treatment-induced mutations, targeting TLS is an attractive avenue for improving chemotherapeutics. However, development of small molecules with high specificity and in vivo efficacy for mutagenic TLS has been challenging. Here, we report the discovery of a small-molecule inhibitor, JH-RE-06, that disrupts mutagenic TLS by preventing recruitment of mutagenic POL ζ. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL ζ. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL ζ recruitment. JH-RE-06 inhibits mutagenic TLS and enhances cisplatin-induced toxicity in cultured human and mouse cell lines. Co-administration of JH-RE-06 with cisplatin suppresses the growth of xenograft human melanomas in mice, establishing a framework for developing TLS inhibitors as a novel class of chemotherapy adjuvants.
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“Recently, a small molecule that disrupts this interaction and sensitizes tumors to cisplatin was developed, also demonstrating in vivo efficacy [120]”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [120]
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“also demonstrating in vivo efficacy [120]”
From CDK-Independent and PCNA-Dependent Functions of p21 in DNA Replication (2020) · cites this paper as [120]
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“or JH-RE-06, which induces REV1 dimerization to block the REV1-REV7 interaction (Fig. 6).109”
From Chasing molecular glue degraders: screening approaches (2022) · cites this paper as [109]
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Self-citationMAD2L2 controls DNA repair at telomeres and DNA breaks by inhibiting 5′ end resection
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Metadata
- Authors
- Wojtaszek, J. L., Chatterjee, N., Najeeb, J., Ramos, A., Lee, M., Bian, K., Xue, J. Y., Fenton, B. A., Park, H., Li, D., Hemann, M. T., Hong, J., Walker, G. C., & Zhou, P.
- Affiliations
- Duke Medical Center (US)
- Massachusetts Institute of Technology (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- Duke University (US)
- University of Rhode Island (US)
- Corresponding author
- Hemann, Michael T.
- Hong, Jiyong
- Walker, Graham C.
- Zhou, Pei
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 178
- Issue
- 1
- Pages
- 152-159.e11
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6644000
- OpenAlex
- W2948035094
- Cited by
- 194
- References
- 39
- Citations by year
- 2026: 22 · 2025: 20 · 2024: 42 · 2023: 23 · 2022: 29 · 2021: 18 · 2020: 32 · 2019: 8
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- Alexander and Margaret Stewart Trust
- Duke University
- National Cancer Institute
- National Institute of Environmental Health Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer therapeutics and mechanisms
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- Rev1, REV7, small molecule inhibitors, cisplatin, chemoresistance, melanoma, adjuvant chemotherapy, protein dimerization, drug resistance
- MeSH terms
- Y-Family DNA Polymerases, Animals, Antineoplastic Agents, Cell Survival, Cisplatin, DNA Damage, DNA-Directed DNA Polymerase, Female, Humans, Mice, Nude, Mice, Transgenic, Neoplasms, Nucleotidyltransferases, Quinolines, Transfection, Mutagenesis, Xenograft Model Antitumor Assays, Cell Line, Tumor, Tumor Burden, Mice, Gene Knockdown Techniques, Mad2 Proteins
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