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A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.

Cell (2019-06-11)
Jessica L Wojtaszek, Nimrat Chatterjee, Javaria Najeeb, Azucena Ramos, Minhee Lee, Ke Bian, Jenny Y Xue, Benjamin A Fenton, Hyeri Park, Deyu Li, Michael T Hemann, Jiyong Hong, Graham C Walker, Pei Zhou
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal ANTI-FLAG® M2-Peroxidase (HRP) antibody produced in mouse, clone M2, purified immunoglobulin, buffered aqueous glycerol solution
Sigma-Aldrich
2,2-Dimethyl-1,3-dioxane-4,6-dione, 98%
Sigma-Aldrich
Suberic acid bis(N-hydroxysuccinimide ester), ≥95%, powder
Sigma-Aldrich
JH-RE-06, ≥98% (HPLC)
Sigma-Aldrich
Isovaleryl chloride, 98%
Sigma-Aldrich
MISSION® esiRNA, targeting human REV1

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