Journal
CELL
Volume 178, Issue 1, Pages 152-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.05.028
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Funding
- National Cancer Institute [CA191448, CA213042]
- Alexander and Margaret Stewart Trust
- National Institute of Environmental Health Sciences [ES028303, ES028865]
- Duke University
- Center for Precision Cancer Medicine at MIT
- National Institutes of Health [S10_RR25528, S10_ RR028976]
- US Department of Energy, Office of Science [W-31-109-Eng-38]
- US Department of Energy, Office of Basic Energy Sciences [W-31-109-Eng-38]
- NSF
- NIH
- NC Biotechnology Center
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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 zeta. Remarkably, JH-RE-06 targets a nearly featureless surface of REV1 that interacts with the REV7 subunit of POL zeta. Binding of JH-RE-06 induces REV1 dimerization, which blocks the REV1-REV7 interaction and POL zeta 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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